Heteroaryl fused aminoalkyl imidazole derivatives: selective modulators of GABAa receptors

ABSTRACT

Disclosed are compounds of the formula: 
                         
or the pharmaceutically acceptable non-toxic salts thereof wherein the A, B, C, D, X, R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 , are variables defined herein, which compounds are highly selective agonists, antagonists or inverse agonists for GABAa brain receptors or prodrugs of agonists, antagonists or inverse agonists for GABAa brain receptors, and are therefore useful in the diagnosis and treatment of anxiety, Down Syndrome, sleep, cognitive and seizure disorders, depression, overdose with benzodiazepine drugs, and enhancement of memory and alertness.

This application claims the benefit of U.S. Provisional Application No.60/127,526, filed Apr. 2, 1999.

FIELD OF THE INVENTION

This invention relates to heteroaryl fused aminoalkylimidazolederivatives which when appropriately substituted selectively bind toGABA_(A) receptors. This invention also relates to pharmaceuticalcompositions comprising such compounds and to the use of such compoundsin enhancing alertness and treating anxiety, overdoses ofbenzodiazepine-type drugs, Down Syndrome, depression, sleep, seizure andcognitive disorders both in human as well as domestic pets andlivestock.

The compounds of this invention are also useful as probes for thelocalization of cell surface receptors.

BACKGROUND

The GABA_(A) receptor superfamily represents one of the classes ofreceptors through which the major inhibitory neurotransmitter,γ-aminobutyric acid, or GABA, acts. Widely, although unequally,distributed through the mammalian brain, GABA mediates many of itsactions through a complex of proteins called the GABA_(A) receptor,which causes alteration in chloride conductance and membranepolarization.

A number of cDNAs for GABA_(A) receptor subunits have beencharacterized. To date at least 6α, 3β, 3γ, 1ε, 1δ and 2ρ subunits havebeen identified. It is generally accepted that native GABA_(A) receptorsare typically composed of 2α, 2β, and 1γ subunits (Pritchett & SeeburgScience 1989; 245:1389-1392 and Knight et. al., Recept. Channels 1998;6:1-18). Evidence such as message distribution, genome localization andbiochemical study results suggest that the major naturally occurringreceptor combinations are α₁β₂γ₂, α₂β₃γ₂, α₃β₃γ₂, and α₅β₃γ₂ (Mohler et.al. Neuroch. Res. 1995; 20(5): 631-636).

Benzodiazepines exert their pharmacological actions by interacting withthe benzodiazepine binding sites associated with the GABA_(A) receptor.In addition to the benzodiazepine site, the GABA_(A) receptor containssites of interaction for several other classes of drugs. These include asteroid binding site, a picrotoxin site, and the barbiturate site. Thebenzodiazepine site of the GABA_(A) receptor is a distinct site on thereceptor complex that does not overlap with the site of interaction forGABA or for other classes of drugs that bind to the receptor (see, e.g.,Cooper, et al., The Biochemical Basis of Neuropharmacology, 6^(th) ed.,1991, pp. 145-148, Oxford University Press, New York). Earlyelectrophysiological studies indicated that a major action of thebenzodiazepines was enhancement of GABAergic inhibition. Compounds thatselectively bind to the benzodiazepine site and enhance the ability ofGABA to open GABA_(A) receptor channels are agonists of GABA receptors.Other compounds that interact with the same site but negatively modulatethe action of GABA are called inverse agonists. Compounds belonging to athird class bind selectively to the benzodiazepine site and yet havelittle or no effect on GABA activity, but can block the action ofGABA_(A) receptor agonists or inverse agonists that act at this site.These compounds are referred to as antagonists.

The important allosteric modulatory effects of drugs acting at thebenzodiazepine site were recognized early and the distribution ofactivities at different receptor subtypes has been an area of intensepharmacological discovery. Agonists that act at the benzodiazepine siteare known to exhibit anxiolytic, sedative, and hypnotic effects, whilecompounds that act as inverse agonists at this site elicit anxiogenic,cognition enhancing, and proconvulsant effects. While benzodiazepineshave a long history of pharmaceutical use as anxiolytics, thesecompounds often exhibit a number of unwanted side effects. These mayinclude cognitive impairment, sedation, ataxia, potentiation of ethanoleffects, and a tendency for tolerance and drug dependence.

GABA_(A) selective ligands may also act to potentiate the effects ofcertain other CNS active compounds. For example, there is evidence thatselective serotonin reuptake inhibitors (SSRIs) may show greaterantidepressant activity when when used in combination with GABA_(A)selective ligands than when used alone.

SUMMARY OF THE INVENTION

This invention relates to heteroaryl fused aminoalkyl-derivatives.Preferred compounds of the invention that bind with high affinity to thebenzodiazepine site of the GABA_(A) receptor, including human GABA_(A)receptors. Preferred compounds of the invention also bind with highselectivity to the benzodiazepine site of the GABA_(A) receptor.

The invention provides novel compounds of Formula I (shown below), andpharmaceutical compositions comprising compounds of Formula I.

The invention further comprises methods of treating patients sufferingfrom certain CNS disorders with an effective amount of a compound of theinvention. The patient may be a human or other mammal. Treatment ofhumans, domesticated companion animals (pets) or livestock animalssuffering such conditions with an effective amount of a compound of theinvention is contemplated by the invention.

In a separate aspect, the invention provides a method of potentiatingthe actions of other CNS active compounds. This method comprisesadministering an effective amount of a compound of the invention withanother CNS active compound.

Additionally this invention relates to the use of the compounds of theinvention as probes for the localization of GABA_(A) receptors in tissuesections. Such probes are useful for in vitro studies, such as bindingassays and autoradiography of tissue sections and for in vivo techniquessuch as PET and SPECT scans.

Packaged pharmaceutical compositions including instructions for use ofthe composition are also included.

In a separate aspect, the invention provides a method of potentiatingthe actions of other CNS active compounds. This method comprisesadministering an effective amount of a compound of the invention withanother CNS active compound.

The invention furthermore provides methods of using compounds of thisinvention as positive controls in assays for receptor activity and usingappropriately labeled compounds of the invention as probes for thelocalization of receptors, particularly GABA_(A) receptors, in tissuesections. Such probes are useful for in vitro studies, such as bindingassays and autoradiography of tissue sections and for in vivo techniquessuch as PET and SPECT scans.

Accordingly, a broad embodiment of the invention is directed tocompounds of Formula I:

or the pharmaceutically acceptable non-toxic salts thereof wherein:

-   W represents

where Z is O, or S;

-   R₁ represents phenyl, C₁-C₆ alkyl, cyclopentyl, cyclohexyl, benzyl,    3-fluorobenzyl, or cyclopropylmethyl;-   R₂ represents hydroxyl, C₁-C₆ alkyl or C₁-C₆ alkoxy, either of which    could be substituted with amino or mono or di(C₁-C₆) alkylamino,    additionally the alkyl portion can form a 5, 6, 7 member ring; or    O(CH₂)_(n)CO₂R₈ where n=1, 2, 3, 4, NR₈COR₉, COR₈, CONR₈R₉ or CO₂R₈    where R₈ and R₉ are the same or different and represent hydrogen or    C₁-C₆ alkyl, additionally R₈ and R₉ can be a 5, 6, 7 member    heterocyclic ring;-   R₃ represents C₁-C₆ alkyl, allyl, cyclopropylmethyl, cyclopentyl; or    benzyl optionally mono-, di-, or trisubstituted independently with    halogen, nitro, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl,    C₁-C₆ alkyl or C₁-C₆ alkoxy, either of which could be substituted    with amino or mono or di(C₁-C₆)alkylamino, additionally the alkyl    portion can form a 5, 6, 7 member ring; or O(CH₂)_(n)CO₂R₈ where    n=1, 2, 3, 4, NR₈COR₉, COR₈, CONR₈R₉ or CO₂R₈ where R₈ and R₉ are    the same or different and represent hydrogen or C₁-C₆ alkyl,    additionally R₈ and R₉ can be a 5, 6, 7 member heterocyclic ring,    additional substitution on the benzyl ring can be directly bound or    O(CH₂)_(n) (where n=1, 2, 3, 4) linked SO₂R₈, NHSO₂R₈, SO₂NHR₈,    SO₂NHCOR₈, CONHSO₂R₈, as well-as tetrazole, triazole, imidazole,    thiazole, oxazole, thiophene, and pyridyl;-   R₄, R₅ and R₆ are the same or different and represent hydrogen,    C₁-C₆ alkyl or C₁-C₆ alkoxy, either of which could be substituted    with amino or mono or di(C₁-C₆)alkylamino, additionally the alkyl    portion can form a 5, 6, 7 member ring, C₁-C₆ alkylthiol, or    halogen, or O(CH₂)_(n)CO₂R₈ where n=1, 2, 3, 4, NR₈COR₉, COR₈,    CONR₈R₉ or CO₂R₈ where R₈ and R₉ are the same or different and    represent hydrogen or straight or branched chain lower alkyl having    1-6 carbon atoms, additionally R₈ and R₉ can be a 5, 6, 7 member    heterocyclic ring, additionally R₄ and R₅ can form a 1,3-dioxolene    ring;-   X represents a bond, CH₂, or CHCH;-   A, B, C, D are the same or different and represent CH or N with the    proviso that not more than two of A, B, C, or D represent N.

Preferred compounds of the invention are highly selective agonists,antagonists or inverse agonists for GABA_(A) brain receptors or prodrugsof agonists, antagonists or inverse agonists for GABAa brain receptors,the benzodiazepine receptor. These compounds are useful in the diagnosisand treatment of anxiety, Down Syndrome, depression, sleep and seizuredisorders, cognitive disorders overdose with benzodiazepine drugs, andenhancement of alertness, both in human and non-human animals anddomestic pets, especially dogs and cats and farm animals such as sheep,swine and cattle.

Thus, the invention also provides methods and compositions for treatingand diagnosing anxiety, Down Syndrome, depression, sleep, cognitive andseizure disorders, and overdose with benzodiazepine drugs.

In another aspect, the invention encompasses compounds that areintermediates in the synthesis of the compounds of Formula I.

DETAILED DESCRIPTION OF THE INVENTION

The compounds encompassed by the instant invention are represented bythe general formula I:

or pharmaceutically acceptable non-toxic salts thereof wherein:

-   W represents

where

-   Z is O, or S;-   R₁ represents phenyl, C₁-C₆ alkyl, cyclopentyl, cyclohexyl, benzyl,    3-fluorobenzyl, or cyclopropylmethyl;-   R₂ represents hydroxyl;    -   C₁-C₆ alkyl or C₁-C₆ alkoxy, each of which are optionally        substituted with amino, mono or di(C₁-C₆)alkylamino, a C₅-C₇        heterocycloalkyl group where the heteroatom is nitrogen and the        nitrogen is attached to the parent alkyl portion;    -   O(CH₂)_(n)CO₂R₈ where n=1, 2, 3, 4, NR₈COR₉, COR₈, CONR₈R₉ or        CO₂R₈ where R₈ and R₉ are the same or different and represent        hydrogen or C₁-C₆ alkyl; or    -   NR₈R₉ forms a 5-, 6-, or 7-membered heterocyclic ring;-   R₃ represents    -   C₁-C₆ alkyl, allyl, cyclopropylmethyl, cyclopentyl; or    -   benzyl optionally mono-, di-, or trisubstituted independently        with        -   halogen, nitro, trifluoromethyl, trifluoromethoxy, cyano, or            hydroxy;        -   C₁-C₆ alkyl or C₁-C₆ alkoxy, each of which is optionally            substituted with amino, mono or di(C₁-C₆) alkylamino, a            C₅-C₇ heterocycloalkyl group where the heteroatom is            nitrogen and the nitrogen is attached to the parent alkyl            portion;        -   O(CH₂)_(n)CO₂R₈ where n=1, 2, 3, 4, NR₈COR₉, COR₈, CONR₈R₉            or CO₂R₈ where R₈ and R₉ are the same or different and            represent hydrogen or C₁-C₆ alkyl;        -   NR₈R₉ forms a 5-, 6-, 7-membered heterocyclic ring;        -   SO₂R₈, NHSO₂R₈, SO₂NHR₈, SO₂NHCOR₈, CONHSO₂R₈ where R₈ is            defined as above;        -   O(CH₂)_(n)-G where n=1, 2, 3, 4 and G is SO₂R₈, NHSO₂R₈,            SO₂NHR₈, SO₂NHCOR₈, or CONHSO₂R₈, where R₈ is as defined            above; or        -   tetrazole, triazole, imidazole, thiazole, oxazole,            thiophene, or pyridyl;-   R₄, R₅ and R₆ are the same or different and represent hydrogen; or    -   C₁-C₆ alkyl or C₁-C₆ alkoxy, each of which is optionally        substituted with amino, mono or di(C₁-C₆)alkylamino, a C₅-C₇        heterocycloalkyl group where the heteroatom is nitrogen and the        nitrogen is attached to the parent alkyl portion, C₁-C₆        alkylthiol, or halogen;    -   O(CH₂)_(n)CO₂R₈ where n=1, 2, 3, 4, NR₈COR₉, COR₈, CONR₈R₉ or        CO₂R₈ where R₈ and R₉ are the same or different and represent        hydrogen or C₁-C₆ alkyl;    -   NR₉R₉ forms a 5-, 6-, or 7-membered heterocyclic ring; or    -   R₄ and R₅ can form a 1,3-dioxolene ring;-   X represents a bond, CH₂, or CHCH; and-   A, B, C, and D are the same or different and represent CH or N with    the proviso that not more than two of A, B, C, or D represent N.

In formula I, R₂ may also represent

hydrogen or

a group of the formula

-   -   where    -   R_(n) and R_(k) independently represent C₁-C₆ alkyl, C₂-C₆        alkenyl, C₁-C₆ cycloalkyl(C₁-C₆)alkyl, benzoyl where the phenyl        portion is optionally substituted with halgoen, C₁-C₆ alkyl, or        C₁-C₆ alkoxy;    -   a group of the formula IV-a

-   -   -   where p, s, and t independently represent 1 or 2;        -   J is CH, N, O, S, or a carbon atom substituted with C₁-C₆            alkyl; or

    -   NR_(k)R_(n) represents

-   -   where s, t, and J are as defined above.

Preferred compounds of the invention are represented by Formula II.

-   R₁ represents phenyl, C₁-C₆ alkyl, cyclopentyl, cyclohexyl, benzyl,    3-fluorobenzyl, or cyclopropylmethyl;-   R₂ represents hydroxyl, C₁-C₆ alkyl or C₁-C₆ alkoxy, either of which    could be substituted with amino or mono or di(C₁-C₆) alkylamino,    additionally the alkyl portion can form a 5, 6, 7 member ring; or    O(CH₂)_(n)CO₂R₈ where n=1, 2, 3, 4, NR₈COR₉, COR₈, CONR₈R₉ or CO₂R₈    where R₈ and R₉ are the same or different and represent hydrogen or    C₁-C₆ alkyl, additionally R₈ and R₉ can be a 5, 6, 7 member    heterocyclic ring;-   R₃ represents C₁-C₆ alkyl, allyl, cyclopropylmethyl, cyclopentyl; or    benzyl optionally mono-, di-, or trisubstituted independently with    halogen, nitro, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl,    C₁-C₆ alkyl or C₁-C₆ alkoxy, either of which could be substituted    with amino or mono or di(C₁-C₆)alkylamino, additionally the alkyl    portion can form a 5, 6, 7 member ring; or O(CH₂)_(n)CO₂R₈ where    n=1, 2, 3, 4, NR₈COR₉, COR₈, CONR₈R₉ or CO₂R₈ where R₈ and R₉ are    the same or different and represent hydrogen or C₁-C₆ alkyl,    additionally R₈ and R₉ can be a 5, 6, 7 member heterocyclic ring,    additional substitution on the benzyl ring can be directly bound or    O(CH₂)_(n) (where n=1, 2, 3, 4) linked SO₂R₈, NHSO₂R₈, SO₂NHR₈,    SO₂NHCOR₈, CONHSO₂R₈, as well as tetrazole, triazole, imidazole,    thiazole, oxazole, thiophene, and pyridyl;-   R₄, R₅ and R₆ are the same or different and represent hydrogen,    C₁-C₆ alkyl or C₁-C₆ alkoxy, either of which could be substituted    with amino or mono or di(C₁-C₆)alkylamino, additionally the alkyl    portion can form a 5, 6, 7 member ring, C₁-C₆ alkylthiol, or    halogen, or O(CH₂)_(n)CO₂R₈ where n=1, 2, 3, 4, NR₈COR₉, COR₈,    CONR₈R₉ or CO₂R₈ where R₈ and R₉ are the same or different and    represent hydrogen or straight or branched chain lower alkyl having    1-6 carbon atoms, additionally R₈ and R₉ can be a 5, 6, 7 member    heterocyclic ring, additionally R₄ and R₅ can form a 1,3-dioxolene    ring;-   X represents a bond, CH₂, CHCH;-   A, B, C, D are the same or different and represent CH or N with the    proviso that not more than two of A, B, C, or D represent N.

Other preferred compounds of the invention are represented by FormulaIII.

where Z is O, or S;

-   R₁ represents phenyl, C₁-C₆ alkyl, cyclopentyl, cyclohexyl, benzyl,    3-fluorobenzyl, or cyclopropylmethyl;-   R₂ represents hydroxyl, C₁-C₆ alkyl or C₁-C₆ alkoxy, either of which    could be substituted with amino or mono or di(C₁-C₆) alkylamino,    additionally the alkyl portion can form a 5, 6, 7 member ring; or    O(CH₂)_(n)CO₂R₈ where n=1, 2, 3, 4, NR₈COR₉, COR₈, CONR₈R₉ or CO₂R₈    where R₈ and R₉ are the same or different and represent hydrogen or    C₁-C₆ alkyl, additionally R₈ and R₉ can be a 5, 6, 7 member    heterocyclic ring;-   R₃ represents C₁-C₆ alkyl, allyl, cyclopropylmethyl, cyclopentyl; or    benzyl optionally mono-, di-, or trisubstituted independently with    halogen, nitro, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl,    C₁-C₆ alkyl or C₁-C₆ alkoxy, either of which could be substituted    with amino or mono or di(C₁-C₆)alkylamino, additionally the alkyl    portion can form a 5, 6, 7, member ring; or O(CH₂)_(n)CO₂R₈ where    n=1, 2, 3, 4, NR₈COR₉, COR₈, CONR₈R₉ or CO₂R₈ where R₈ and R₉ are    the same or different and represent hydrogen or C₁-C₆ alkyl,    additionally R₈ and R₉ can be a 5, 6, 7 member heterocyclic ring,    additional substitution on the benzyl ring can be directly bound or    O(CH₂)_(n) (where n=1, 2, 3, 4) linked SO₂R₈, NHSO₂R₈, SO₂NHR₈,    SO₂NHCOR₈, CONHSO₂R₈, as well as tetrazole, triazole, imidazole,    thiazole, oxazole, thiophene, and pyridyl;-   R₄, R₅ and R₆ are the same or different and represent hydrogen,    C₁-C₆ alkyl or C₁-C₆ alkoxy, either of which could be substituted    with amino or mono or di(C₁-C₆)alkylamino, additionally the alkyl    portion can form a 5, 6, 7 member ring, C₁-C₆ alkylthiol, or    halogen, or O(CH₂)_(n)CO₂R₉ where n=1, 2, 3, 4, NR₈COR₉, COR₈,    CONR₈R₉ or CO₂R₈ where R₈ and R₉ are the same or different and    represent hydrogen or straight or branched chain lower alkyl having    1-6 carbon atoms, additionally R₈ and R₉ can be a 5, 6, 7 member    heterocyclic ring, additionally R₄ and R₅ can form a 1,3-dioxolene    ring;-   X represents a bond, CH₂, CHCH;-   A, B, C, D are the same or different and represent CH or N with the    proviso that not more than two of A, B, C, or D represent N.

More preferred compounds of Formula I are represented by Formula IV

where

-   R₄, R₅, and R₆ are as defined above for Formula I;-   R₁ and R₃ are independently C₁-C₆ alkyl;-   and R_(a) and R_(b) are independently

hydrogen or

a group of the formula

-   -   where    -   R_(n) and R_(k) independently represent C₁-C₆ alkyl, C₂-C₆        alkenyl, C₁-C₆ cycloalkyl(C₁-C₆)alkyl, benzoyl where the phenyl        portion is optionally substituted with halgoen, C₁-C₆ alkyl, or        C₁-C₆ alkoxy;    -   a group of the formula IV-a

-   -   -   where p, s, and t independently represent 1 or 2;        -   J is CH, N, O, or a carbon atom substituted with C₁-C₆            alkyl; or

    -   NR_(k)R_(n) represents

-   -   where s, t, and J are as defined above.

Preferred compounds of Formula IV include those where R₁ is propyl andR₃ is C₃-C₅ alkyl, preferably isobutyl. More preferred compounds of IVare those where R_(b) is hydrogen and R_(a) is —NHR_(n) where R_(n) isdefined as above or —NR_(k)R_(n) where both R_(n) and R_(k) are allyl orC₁-C₆ alkyl.

Preferred —NR_(k)R_(n) groups include diallylamino, dimethylamino,diethylamino, and N-ethyl-N-cyclopropylmethylamino.

Preferred NHR_(n) groups include those where R_(n) is allyl, C₁-C₆alkyl, or a group of IV-a. Preferred IV-a groups include pyrrolidinyl,morpholinyl and piperidinyl.

Particularly preferred compounds of IV are those where R₁ is propyl, R₃is isobutyl, R_(b) is hydrogen, and R_(a) is

In certain situations, the compounds of Formula I may contain one ormore asymmetric carbon atoms, so that the compounds can exist indifferent stereoisomeric forms. These compounds can be, for example,racemates or optically active forms. In these situations, the singleenantiomers, i.e., optically active forms, can be obtained by asymmetricsynthesis or by resolution of the racemates. Resolution of the racematescan be accomplished, for example, by conventional methods such ascrystallization in the presence of a resolving agent, or chromatography,using, for example a chiral HPLC column.

Representative compounds of the present invention, which are encompassedby Formula I, include, but are not limited to the compounds described inthe Examples and their pharmaceutically acceptable acid addition salts.In addition, if the compound of the invention is obtained as an acidaddition salt, the free base can be obtained by basifying a solution ofthe acid salt. Conversely, if the product is a free base, an additionsalt, particularly a pharmaceutically acceptable addition salt, may beproduced by dissolving the free base in a suitable organic solvent andtreating the solution with an acid, in accordance with conventionalprocedures for preparing acid addition salts from base compounds.

Non-toxic pharmaceutical salts include salts of acids such ashydrochloric, phosphoric, hydrobromic, sulfuric, sulfinic, formic,toluenesulfonic, methanesulfonic, nitric, benzoic, citric, tartaric,maleic, hydroiodic, alkanoic such as acetic, HOOC—(CH₂)_(n)—COOH where nis 0-4, and the like. Those skilled in the art will recognize a widevariety of non-toxic pharmaceutically acceptable addition salts.

The present invention also encompasses the acylated prodrugs of thecompounds of Formula I. Those skilled in the art will recognize varioussynthetic methodologies which may be employed to prepare non-toxicpharmaceutically acceptable addition salts and acylated prodrugs of thecompounds encompassed by Formula I.

By “alkyl” or “lower alkyl” in the present invention is meant C₁-C₆alkyl, i.e., straight or branched chain alkyl groups having 1-6 carbonatoms, such as, for example, methyl, ethyl, propyl, isopropyl, n-butyl,sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl,2-hexyl, 3-hexyl, and 3-methylpentyl. Preferred C₁-C₆ alkyl groups aremethyl, ethyl, propyl, butyl, cyclopropyl or cyclopropylmethyl.

By “alkoxy” or “lower alkoxy” in the present invention is meant C₁-C₆alkoxy, i.e., straight or branched chain alkoxy groups having 1-6 carbonatoms, such as, for example, methoxy, ethoxy, propoxy, isopropoxy,n-butoxy, sec-butoxy, tert-butoxy, pentoxy, 2-pentyl, isopentoxy,neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, and 3-methylpentoxy.

By (hetero) cyclic ring is meant a ring that is either aliphatic oraromatic and optionally contains at least one hetero atom. Hetero atomsinclude nitrogen, sulfur, and oxygen. Examples of such (hetero) cyclicrings are cyclohexyl, cyclopenyl, cyclohexyl, piperidinyl, piperazinyl,pyrrolidinyl, morpholinyl, etc.

By heteroaryl (aromatic heterocycle) in the present invention is meantone or more aromatic ring systems of 5-, 6-, or 7-membered ringscontaining at least one and up to four hetero atoms selected fromnitrogen, oxygen, or sulfur. Such heteroaryl groups include, forexample, thienyl, furanyl, thiazolyl, imidazolyl, (is)oxazolyl, pyridyl,pyrimidinyl, imidazolyl, (iso)quinolinyl, naphthyridinyl,benzimidazolyl, and benzoxazolyl.

Specific examples of heteroaryl groups are the following:

wherein

L is nitrogen or —CR¹¹;

T is —NR¹⁹, oxygen, or sulfur;

-   -   R¹¹ and R^(11f) are the same or different and are selected from        hydrogen, halogen, hydroxy, C₁-C₆ alkyl, (C₁-C₆)alkoxy, amino,        or mono- or di(C₁-C₆)alkylamino;    -   R², R^(2f), and R¹³ are the same or different and are selected        from hydrogen, halogen, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, amino,        mono- or di(C₁-C₆)alkylamino, hydroxy, or trifluoromethyl; and    -   R¹⁹ is hydrogen, lower alkyl having 1-6 carbon atoms.

The invention encompasses all possible tautomers and rotamersrepresented by Formula I.

By the term “halogen” in the present invention is meant fluorine,bromine, chlorine, and iodine.

Aryl and heteroaryl fused aminoalkyl-imidazoles of Formula I and theirsalts are suitable for the diagnosis and treatment of anxiety, DownSyndrome, sleep and seizure disorders, overdoses of benzodiazepine-typedrugs, depression and cognitive disorders and for the enhancement ofalertness, both in human and non-human animals and domestic pets,especially dogs and cats and farm animals such as sheep, swine andcattle. These interactions result in the pharmacological activites ofthese compounds.

The compounds of general Formula I may be administered orally,topically, parenterally, by inhalation or spray or rectally in dosageunit formulations containing conventional non-toxic pharmaceuticallyacceptable carriers, adjuvants and vehicles. The term parenteral as usedherein includes subcutaneous injections, intravenous, intramuscular,intrasternal injection or infusion techniques. In addition, there isprovided a pharmaceutical formulation comprising a compound of generalFormula I and a pharmaceutically acceptable carrier. One or morecompounds of general Formula I may be present in association with one ormore non-toxic pharmaceutically acceptable carriers and/or diluentsand/or adjuvants and if desired other active ingredients. Thepharmaceutical compositions containing compounds of general Formula Imay be in a form suitable for oral use, for example, as tablets,troches, lozenges, aqueous or oily suspensions, dispersible powders orgranules, emulsion, hard or soft capsules, or syrups or elixirs.

Compositions intended for oral use may be prepared according to anymethod known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavoringagents, coloring agents and preserving agents in order to providepharmaceutically elegant and palatable preparations. Tablets contain theactive ingredient in admixture with non-toxic pharmaceuticallyacceptable excipients which are suitable for the manufacture of tablets.These excipients may be for example, inert diluents, such as calciumcarbonate, sodium carbonate, lactose, calcium phosphate or sodiumphosphate; granulating and disintegrating agents, for example, cornstarch, or alginic acid; binding agents, for example starch, gelatin oracacia, and lubricating agents, for example magnesium stearate, stearicacid or talc. The tablets may be uncoated or they may be coated by knowntechniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonosterate or glyceryl distearate may be employed.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example peanut oil, liquid paraffin or olive oil.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydropropylmethylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example, lecithin, or condensation products of an alkylene oxidewith fatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredientsin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide palatable oralpreparations. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present.

Pharmaceutical compositions of the invention may also be in the form ofoil-in-water emulsions. The oily phase may be a vegetable oil, forexample olive oil or arachis oil, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitol,anhydrides, for example sorbitan monoleate, and condensation products ofthe said partial esters with ethylene oxide, for example polyoxyethylenesorbitan monoleate. The emulsions may also contain sweetening andflavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative and flavoring and coloringagents. The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleaginous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also be sterile injectablesolution or suspension in a non-toxic parentally acceptable diluent orsolvent, for example as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono-or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

The compounds of general Formula I may also be administered in the formof suppositories for rectal administration of the drug. Thesecompositions can be prepared by mixing the drug with a suitablenon-irritating excipient which is solid at ordinary temperatures butliquid at the rectal temperature and will therefore melt in the rectumto release the drug. Such materials are cocoa butter and polyethyleneglycols.

Compounds of general Formula I may be administered parenterally in asterile medium. The drug, depending on the vehicle and concentrationused, can either be suspended or dissolved in the vehicle.Advantageously, adjuvants such as local anesthetics, preservatives andbuffering agents can be dissolved in the vehicle.

Dosage levels of the order of from about 0.1 mg to about 140 mg perkilogram of body weight per day are useful in the treatment of theabove-indicated conditions (about 0.5 mg to about 7 g per patient perday). The amount of active ingredient that may be combined with thecarrier materials to produce a single dosage form will vary dependingupon the host treated and the particular mode of administration. Dosageunit forms will generally contain between from about 1 mg to about 500mg of an active ingredient.

Frequency of dosage may also vary depending on the compound used and theparticular disease treated. However, for treatment of most disorders, adosage regimen of 4 times daily or less is preferred. For the treatmentof anxiety or depression a dosage regimen of 1 or 2 times daily isparticularly preferred. For the treatment of sleep disorders a singledose that rapidly reaches effective concentrations is desirable.

It will be understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors including theactivity of the specific compound employed, the age, body weight,general health, sex, diet, time of administration, route ofadministration, and rate of excretion, drug combination and the severityof the particular disease undergoing therapy.

Preferred compounds of the invention will have certain pharmacologicalproperties. Such properties include, but are not limited to oralbioavailability, low toxicity, low serum protein binding and desirablein vitro and in vivo half-lifes. Penetration of the blood brain barrierfor compounds used to treat CNS disorders is necessary, while low brainlevels of compounds used to treat periphereal disorders are oftenpreferred.

Assays may be used to predict these desirable pharmacologicalproperties. Assays used to predict bioavailability include transportacross human intestinal cell monolayers, including Caco-2 cellmonolayers. Toxicity to cultured hepatocyctes may be used to predictcompound toxicity. Penetration of the blood brain barrier of a compoundin humans may be predicted from the brain levels of the compound inlaboratory animals given the compound intravenously. Serum proteinbinding may be predicted from albumin binding assays. Such assays aredescribed in a review by Oravcova, et al. (Journal of Chromatography B(1996) volume 677, pages 1-27).

Compound half-life is inversely proportional to the frequency of dosageof a compound. In vitro half-lifes of compounds may be predicted fromassays of microsomal half-life as described by Kuhnz and Gieschen (DrugMetabolism and Disposition, (1998) volume 26, pages 1120-1127).

The present invention also pertains to packaged pharmaceuticalcompositions for treating disorders responsive to GABA_(A) receptormodulation, e.g., treatment of cognitive deficits, anxiety or depressionby GABA_(A) receptor modulation. The packaged pharmaceuticalcompositions include a container holding a therapeutically effectiveamount of at least one GABA_(A) receptor modulator as described supraand instructions (e.g., labeling) indicating the contained GABA_(A)receptor ligand is to be used for treating a disorder responsive toGABA_(A) receptor modulation in the patient.

The present invention also pertains to methods for altering thesignal-tranducing activity of GABA_(A) receptors, said method comprisingexposing cells expressing such receptor to an effective amount of acompound of the invention.

A method of inhibiting the binding of a benzodiazepine compound to thebenzodiazepine site of the GABA_(A) receptor, comprising contacting acompound of Formula I with cells expressing such a receptor in thepresence of a the benzodiazepine compound, wherein the compound ispresent at a concentration sufficient to inhibit benzodiazepine compoundbinding to cells expressing a cloned human GABA_(A) receptor in vitro isprovided by a separate aspect of the invention.

In a separate aspect, the invention provides a method of potentiatingthe actions of other CNS active compounds, which comprises administeringan effective amount of a compound of the invention in combination withanother CNS active compound. Such CNS active compounds include, but arenot limited to the following: for anxiety, serotonin receptor (e.g.5-HT_(1A)) agonists and antagonists; for anxiety and depression,neurokinin receptor antagonists or corticotropin releasing factorreceptor (CRF₁) antagonists; for sleep disorders, melatonin receptoragonists; and for neurodegenerative disorders, such as Alzheimer'sdementia, nicotinic agonists, muscarinic agents, acetylcholinesteraseinhibitors and dopamine receptor agonists. Particularly the inventionprovides a method of potentiating the antidepressant activity ofselective serotonin reuptake inhibitors (SSRIs) by administering aneffective amount of a GABA agonist compound of the invention incombination with an SSRI.

Combination administration can be carried out in an analogous fashion tothat disclosed in Da-Rocha, et al., J. Psychopharmacology (1997) 11(3)211-218; Smith, et al., Am. J. Psychiatry (1998) 155(10) 1339-45; andLe, et al., Alcohol and Alcoholism (1996) 31 Suppl. 127-132. Also see,the discussion of the use of the GABA_(A) receptor ligand3-(S-methylisoxazol-3-yl)-6-(1-methyl-1,2,3-triazol-4-yl)methyloxy-1,2,4-triazolo[3,4-a]phthalzinein combination with nicotinic agonists, muscarinic agonists, andacetylcholinesterase inhibitors, in PCT International publications Nos.WO 99/47142, WO 99/47171, and WO 99/47131, respectively. Also see inthis regard PCT International publication No. WO 99/37303 for itsdiscussion of the use of a class of GABA_(A) receptor ligands,1,2,4-triazolo[4,3-b]pyridazines, in combination with SSRIs.

The disclosures of all articles and references mentioned in in thisapplication, including patents, are incorporated herein by reference.

The invention is illustrated further by the following examples which arenot to be construed as limiting the invention in scope or spirit to thespecific procedures described in them. Compounds of the invention can beprepared using the reactions depicted in Schemes I to VI.

Those having skill in the art will recognize that the starting materialsmay be varied and additional steps employed to produce compoundsencompassed by the present invention, as demonstrated by the followingexamples.

The following examples illustrate the general procedures for thepreparation of compounds of the invention using the reactions outlinedabove in Schemes I-VI. These examples are not to be construed aslimiting the invention in scope or spirit to the specific procedures andcompounds described in them.

Analysis is performed on a Hewlett Packard 6890 GC, equipped with a dualcool on-column inlets and flame ionization detectors or mass specdetectors. All gas flows are regulated via electronic pneumatic control.The analytical column used is a Supelco PTE-5 QTM, 15 m×0.53 mm ID×0.50μm film. GC instrument control and data collection are handled using aPerkin Elmer TurboChrom Client/Server data system. GC conditions:On-column injector 163 C for 2.5 min., ramp at 40 C/min to 323 C. Ovenprogram 100 C for 1 minute, ramp at 40 C/min to 320 C. Detectortemperature is set at 325 C. GC conditions: for compounds 7-12 initialtemperature 200 C, ramp to 300 C at 20 C/min on a 12 m, DB-5 column.

EXAMPLE 1 General Procedure for the Preparation ofChloromethylbenzimidazoles as Outlined in Scheme I

1. Imidate Hydrochloride

A solution of 150 mL (2.37 mole) of chloroacetonitrile, 139 mL (2.37mole) of ethanol in 1,200 mL of dry benzene is cooled to 0° C. in anice/ethanol bath. Dry HCl gas is bubbled through the vigorously stirredsolution for approximately 30 min. while the internal temperature ismaintained below 10° C. The solution is allowed to stand at rt.overnight. The resulting solid is filtered and washed with 2 L of dryether and allowed to air dry to afford 328 g (88%) of imidatehydrochloride.

2. 1-n-Propyl-2-(chloromethyl)-5-fluorobenzimidazole:

A solution of 11.25 g (0.07 mole) of2-n-Propyl-5-fluorophenelyenediamine in 200 mL of anhydrous CHCl₃ istreated with 11.06 g (0.07 mole) of imidate at room temperature. Theheterogeneous reaction mixture is allowed to stir for 45 min. at whichtime no starting material is detectable by TLC. 100 mL of saturatedNaHCO₃ is added and extracted 3×50 mL of CH₂Cl₂. The extracts are driedover anhydrous MgSO₄, the solvent removed in vacuo, and the residuechromatgraphed (SiO₂) with 50% ethyl acetate/hexane to afford 15 g (95%)of 1-n-Propyl-2-(chloromethyl)-5-fluorobenzimidazole.

EXAMPLE 2 General Procedure for the Preparation of Benzimidazoles asShown in Scheme II

N-[benzoyl]-N-methyl-1-n-propyl-2-(methanamine)-5-fluorobenzimidazole

A solution of 8 mmole of1-n-Propyl-2-(chloromethyl)-5-fluorobenzimidazole (alternatively named2-(chloromethyl)-5-fluoro-1-propylbenzimidazole) in 20 mL of dryAcetonitrile is treated with 10 mL of 40% aqueous methylamine for 16 hrat room temperature. The solvent is removed in vacuo and the residue ispartitioned between 30 mL of ethyl acetate and 10 mL of 1 N NaOH. Theethyl acetate layer is dried over anhydrous Na₂SO₄ and solvent removedin vacuo to afford 1.68 g 95% of1-n-Propyl-2-(methanamine)-5-fluorobenzimidazole. Benzoylchloride 1.5 eqis treated with of 1-n-Propyl-2-(methanamine)-5-fluorobenzimidazole 1.0eq in dichloromethane at room temperature for 1 hr. The reaction isquenched with 1 N NaOH and partitioned between dichloromethane andwater. The organic layer is dried with Na₂SO₄ and the solvent removed invacuo. The residue is chromatographed (SiO₂) with ethyl acetate toafford 95% ofN-[benzoyl]-N-methyl-1-n-propyl-2-(methanamine)-5-fluorobenzimidazole[alternatively namedN-((5-fluorobenzimidazol-2-yl)methyl)-N-methylbenzamide] (Compound A1).

EXAMPLE 3 General Procedure for the Preparation of Benzimidazoles asShown in Scheme 3

(2,5-difluorophenyl)-N-{[5-(morpholin-4-ylmethyl)-1-propylbenzimidazol-2-yl]methyl}-N-propylcarboxamide

A solution of 20 g (0.095 mole) of[3-nitro-4-(propylamino)phenyl]methan-1-ol and 19.2 g (0.28 mole) ofimidazole in 200 mL of anhydrous DMF is treated with 19 g (0.13 mole) oft-butyldimethylsilyl chloride at room temperature for 30 min. Theresulting mixture is diluted with 400 mL of ethyl acetate and washed3×200 mL of water and 1×200 mL of brine. The resulting orgainc layer isdried over anhydrous Na₂SO₄ and the solvent removed in vacuo. Theresulting oil is column chromatographed 5% ethyl acetate/hexanes toafford 11 g (35%) of{2-nitro-4-[(1,1,2,2-tetramethy-1-silapropoxy)methyl]phenyl}propylamine.

A solution of 11 g (0.033 mole) of{2-nitro-4-[(1,1,2,2-tetramethy-1-silapropoxy)methyl]phenyl}propylaminein 100 mL of ethanol and 1 g 10% Pd/C is treated with 50 psi of H₂ atroom temperature for 2 hr. The resulting mixture is filtered throughcelite, washed with 200 mL of ethanol and the solvent removed in vacuo.The crude material is treated with 9.7 g (0.06 mole) of imidatehydrochloride in 250 mL of chloroform at room temperature for 1 hr. Thereaction mixture is partitioned between 200 mL sat NaHCO₃ and 200 mL ofchloroform. The organic layer is dried over anhydrous anhydrous Na₂SO₄and the solvent removed in vacuo. The resulting oil is columnchromatographed 50% ethyl acetate/hexanes to afford 6 g (52% for 2steps) of1-{([2-(chloromethyl)-1-propylbenzimidazol-5-yl]methoxy}-1,1,2,2-tetramethyl-1-silapropane.

A solution of 2.0 g (5.6 mmole) of1-{[2-(chloromethyl)-1-propylbenzimidazol-5-yl]methoxy}-1,1,2,2-tetramethyl-1-silapropanein 20 mL of anhydrous acetonitrile is treated with 10 mL of propylaminefor 16 hr at room temperature. The solvent is removed in vacuo and theresidue is partitioned between 30 mL of ethyl acetate and 10 mL of 1 NNaOH. The ethyl acetate layer is dried over anhydrous Na₂SO₄ and solventremoved in vacuo to afford 2.1 g (99%) ofpropyl({1-propyl-5-[(1,1,2,2-tetramethyl-1-silapropoxy)methyl]benzimidazol-2-yl}methyl)amine.

2,5-difluorobenzoylchloride 1.5 eq is treated with 1.0 eq 1.25 g (3.3mmole) ofpropyl({1-propyl-5-[(1,1,2,2-tetramethyl-1-silapropoxy)methyl]benzimidazol-2-yl}methyl)aminein dichloromethane at room temperature for 1 hr. The reaction isquenched with 1 N NaOH and partitioned between dichloromethane andwater. The organic layer is dried over anhydrous Na₂SO₄ and the solventremoved in vacuo. The residue is chromatographed (SiO₂) with ethylacetate to afford 74% of(2,5-difluorophenyl)-N-propyl-N-({1-propyl-5-[(1,1,2,2-tetramethyl-1-silapropoxy)methyl]benzimidazol-2-yl}methyl)carboxamide.

A solution 1.25 g (2.4 mmole) of(2,5-difluorophenyl)-N-propyl-N-({1-propyl-5-[(1,1,2,2-tetramethyl-1-silapropoxy)methyl]benzimidazol-2-yl}methyl)carboxamidein 20 mL of THF is treated at room temperature with 3 mL of 1Mtetrabutylammonium fluoride for 1 hr. The reaction solution is dilutedwith 20 mL of sat NaHCO₃ and extracted with 3×100 mL of dichloromethane.The organic extracts are dried over anhydrous Na₂SO₄ and the solventremoved in vacuo to afford 0.96 g (99%) of(2,5-difluorophenyl)-N-{[5-(hydroxymethyl)-1-propylbenzimidazol-2-yl]methyl}-N-propylcarboxamide.

(2,5-difluorophenyl)-N-{[5-(hydroxymethyl)-1-propylbenzimidazol-2-yl]methyl}-N-propylcarboxamide0.96 g (2.3 mmole) is treated with 30 mL of thionyl chloride for 15 mina room temperature. The resulting mixture is concentrated in vacuo andpartitioned between 100 mL sat NaHCO₃ and 100 mL of ethyl acetate. Theethyl acetate layer is dried over anhydrous Na₂SO₄ and concentrated invacuo. The resulting oil is chroamtoagraphed 50% ethyl acetate/hexanesto afford 0.9 g (93%) of(2,5-difluorophenyl)-N-{[5-(chloromethyl)-1-propylbenzimidazol-2-yl]methyl)-N-propylcarboxamide.

A solution of 0.2 mL of 0.2M(2,5-difluorophenyl)-N-{[5-(chloromethyl)-1-propylbenzimidazol-2-yl]methyl)-N-propylcarboxamidein 1-methyl-2-pyrrolidinone is treated at room temperature for 16 hrwith 0.3 mL of 0.2M solution of morpholine in toluene. The resultingmixture is diluted with 2 mL of ethyl acetate and washed 2×2 mL of water1×2 mL brine. The ethyl acetate layer is dried over anhydrous Na₂SO₄ andconcentrated in vacuo to afford 70% of(2,5-difluorophenyl)-N-{[5-(morpholin-4-ylmethyl)-1-propylbenzimidazol-2-yl]methyl}-N-propylcarboxamide.

EXAMPLE 4

The following compounds are prepared essentially according to theprocedure described in Examples 1-5, and as shown in Schemes 1-6:

(a)(2,5-difluorodifluorophenyl)-N-methyl-N-((1-propylbenzimidazol-2-yl)methyl)carboxamide(Compound A5); GC retention time=5.26 minutes.

(b) N-((3-cyclopropylmethylimidazolo[5,4-b]pyridin-2-yl)methyl)(3-fluorophenyl)-N-propylcarboxamide (Compound A6); GC retentiontime=5.07 minutes.

(c)N-[(3-cyclopropylmethylimidazolo[5,4-b]pyridin-2-yl)methyl](2,5-difluorophenyl)-N-propylcarboxamide(Compound A7); GC retention time=4.80 minutes.

(d)N-[(6-chloro-1-propylbenzimidazol-2-yl)methyl](2,5-difluorophenyl)-N-propylcarboxamide(Compound A8); GC retention time=MS (CI) M+453 amu.

(e) N-({5-(diethylamino)methyl]-1-butylbenzimidazol-2-yl}methyl)(3-fluorophenyl)-N-propylcarboxamide (Compound A9); GC retentiontime=5.96 minutes.

(f)N-((3-n-butyl-imidazolo[5,4-b]pyridin-2-yl)methyl](3-iodophenyl)-N-propylcarboxamide(Compound A10); GC retention time=6.12 minutes.(g)N-[(7-chloro-1-propylbenzimidazol-2-yl)methyl](3-fluorophenyl)-N-methylcarboxamideM+361 amu(h)N-[(7-chloro-1-propylbenzimidazol-2-yl)methyl](3-fluorophenyl)-N-propylcarboxamideM+389 amu(i)N-[(6-chloro-1-propylbenzimidazol-2-yl)methyl]{3-[(methylamino)methyl]phenyl)-N-propylcarboxamideM+414 amu(j)(3-fluorophenyl)-N-[(4-fluoro-1-propylbenzimidazol-2-yl)methyl]-N-propylcarboxamideM+372 amu(k)(2,5-difluorophenyl)-N-([1-(cyclopropylmethyl)benzimidazol-2-yl]methyl}-N-propylcarboxamideM+384 amu(l)N-([5-(N,N-diethylcarbamoyl)-1-propylbenzimidazol-2-yl]methyl}(3-fluorophenyl)-N-propylcarboxamideM+454 amu(m)(2,5-difluorophenyl)-N-[(4-fluoro-1-propylbenzimidazol-2-yl)methyl]-N-propylcarboxamideM+391 amu(n)N-{[6-chloro-1-(cyclopropylmethyl)benzimidazol-2-yl]methyl}(3-fluorophenyl)-N-propylcarboxamideM+401 amu(o)(2,5-difluorophenyl)-N-({5-[(ethylamino)methyl]-1-propylbenzimidazol-2-yl}methyl)-N-propylcarboxamideM+430 amu(p)(2,5-difluorophenyl)-N-propyl-N-({1-propyl-5-[(propylamino)methyl]benzimidazol-2-yl}methyl)carboxamideM+444 amu(q)(2,5-difluorophenyl)-N-({5-[(methylamino)methyl]-1-propylbenzimidazol-2-yl}methyl)-N-propylcarboxamideM+416 amu(r)N-[(6-chloro-1-propylbenzimidazol-2-yl)methyl](4-[2-(ethylamino)ethoxy]phenyl)-N-(3-methylbutyl)carboxamideM+486 amu(s)N-[(6-chloro-1-propylbenzimidazol-2-yl)methyl]-N-(3-methylbutyl){4-[2-(propylamino)ethoxy]phenyl}carboxamideM+500 amu(t)N-[(6-chloro-1-propylbenzimidazol-2-yl)methyl](2-methyl(1,3-thiazol-4-yl))-N-(2-methylpropyl)carboxamideM+406 amu(u)(5-bromo(2-thienyl))-N-[(6-chloro-1-propylbenzimidazol-2-yl)methyl]-N-(2-methylpropyl)carboxamideM+470 amu(v)[3-(2-bromoethoxy)phenyl]-N-[(6-chloro-1-propylbenzimidazol-2-yl)methyl]-N-(2-methylpropyl)carboxamideM+508 amu(w)N-[(6-chloro-1-propylbenzimidazol-2-yl)methyl]-N-(2-methylpropyl)(3-[2-(propylamino)ethoxy]phenyl}carboxamideM+486 amu(x)N-[(6-chloro-1-propylbenzimidazol-2-yl)methyl](3-{2-[(2-methoxyethyl)amino]ethoxy}phenyl)-N-(2-methylpropyl)carboxamideM+502 amu(y)N-[(6-chloro-1-propylbenzimidazol-2-yl)methyl](3-{2-[(2-ethoxyethyl)amino]propoxy}phenyl)-N-(2-methylpropyl)carboxamideM+530 amu(z)N-[(6-chloro-1-propylbenzimidazol-2-yl)methyl](3-(2-{[2-(methylethoxy)ethyl]amino}propoxy)phenyl]-N-(2-methylpropyl)carboxamideM+544 amu

EXAMPLES 5-41

The compounds of Examples 5-41 are prepared essentially according to theprocedure described in Examples 1-3, and as shown in Schemes 1-6. Thesecompounds are represented by the formulae presented in each of theexamples with the definitions of the substituents found within thetable. It is noted for the reader that the R₂ and R₃ groups used inthese formulae are not the same R₂ and R₃ groups used in Formula I.

Structures for the compounds of Examples 5-42 are shown in Appendices 1and 2 hereto.

EXAMPLE 5

For each compound, the definitions of R₂ and R₃ are specified in thefollowing table.

Compound No. R₂ R₃ 1 Methyl 3-Fluorophenyl 2 Allyl 3-Fluorophenyl 3Propyl 3-Fluorophenyl 4 Allyl 3-Fluorophenyl 5 Propyl 3-Fluorophenyl 6Propyl 3,4-Difluorophenyl 7 Allyl 2,5-Difluorophenyl 8 Propyl2,5-Difluorophenyl 9 Propyl 1,3-Benzodioxol-5-yl 10 Allyl3-Chloro-4-fluorophenyl 11 Propyl 3-Chloro-4-fluorophenyl 12 Methyl5-Chloro-2-methoxyphenyl 13 3-Methylbutyl 3-{2-[(3-Methoxypropyl)amino]ethoxy} phenyl 14 3-Methylbutyl 3-{2-[(3-Ethoxypropyl)amino]ethoxy} phenyl 15 3-Methylbutyl 3-{2-[(3-Ethoxypropyl)amino]ethoxy} phenyl 16 3-Methylbutyl 3-[2-(Benzylamino)ethoxy]phenyl 17 3-Methylbutyl 3-[2-(Benzylamino) ethoxy]phenyl 182-Methylpropyl 3-{2-[(3-i- Propoxypropyl)amino]ethoxy} phenyl 193-Methylbutyl 3-{2-[(3-i- Propoxypropyl)amino]ethoxy} phenyl 20 Benzyl3-Chloro-2-thienyl 21 4-Fluorobenzyl 3-Chloro-2-thienyl 22 Benzyl3-Chloro-4-methylphenyl 23 2-Fluorobenzyl 3-Chloro-4-methylphenyl 244-Fluorobenzyl 3-Chloro-4-methylphenyl 25 4-Fluorobenzyl2-Fluoro-6-trifluoromethylphenyl 26 4-Fluorobenzyl 3,5-Dibromophenyl 27Pentyl 3-Bromophenyl 28 3-Methylbutyl 3-Bromophenyl 29 2-Methylpropyl4-Bromophenyl 30 3-Methylbutyl 4-Bromophenyl 31 Butyl 2-Bromophenyl 32Pentyl 2-Bromophenyl 33 3-Methylbutyl 2-Bromophenyl 34 3-Methylbutyl3-Methoxyphenyl 35 3-Methylbutyl 2-Methoxyphenyl 36 3-Methylbutyl3-Chlorophenyl 37 3-Methylbutyl 2-Chlorophenyl 38 3-Methylbutyl2-Chlorophenyl 39 Ethyl 5-Chloro-2-methoxyphenyl 40 Allyl5-Chloro-2-methoxyphenyl 41 Propyl 5-Chloro-2-methoxyphenyl 42 Methyl2,5-Dichlorophenyl 43 Allyl 2,5-Dichlorophenyl 44 Propyl2,5-Dichlorophenyl 45 Propyl 5-Methyl-2-thienyl 46 Propyl Phenyl 47Propyl 3-Methylphenyl 48 Propyl 3-Fluoro-4-methylphenyl 49 Allyl5-Fluoro-2-methylphenyl 50 Propyl 5-Fluoro-2-methylphenyl 51 Benzyl2,3,5,6-Tetrafluorophenyl 52 4-Fluorobenzyl 2,3,5,6-Tetrafluorophenyl 53Benzyl 2,4,6-Trifluorophenyl 54 Benzyl 2,3,6-Trifluorophenyl 554-Fluorobenzyl 2,3,6-Trifluorophenyl 56 4-Fluorobenzyl2-Chloro-6-fluorophenyl 57 Benzyl 2-Fluoro-6-trifluoromethylphenyl 582-Methylpropyl 3-(2-{[(4-Methylphenyl) methyl]amino} ethoxy)phenyl 593-Methylbutyl 3-{2-[(2-Cyclohex-1-enylethyl) amino]ethoxy} phenyl 602-Methylpropyl 3-(2-{[(2-Methylphenyl) methyl]amino} ethoxy)phenyl 612-Methylpropyl 3-(2-{[(3-Methylphenyl) methyl]amino} ethoxy)phenyl 622-Methylpropyl 3-(2-{[(2-Methoxyphenyl) methyl]amino} ethoxy)phenyl 632-Fluorobenzyl 3-Iodo-4-methylphenyl 64 4-Fluorobenzyl3-Iodo-4-methylphenyl 65 4-Fluorobenzyl 2-Thienyl 66 Benzyl 2-Thienyl 674-Fluorobenzyl 2-Thienyl 68 Benzyl 3-Methyl-2-thienyl 69 4-Fluorobenzyl3-Methyl-2-thienyl 70 Benzyl 5-Methyl-2-thienyl 71 2-Fluorobenzyl5-Methyl-2-thienyl 72 4-Fluorobenzyl 5-Methyl-2-thienyl 734-Fluorobenzyl 4,5-Dimethyl-2-furyl 74 2-Methylpropyl 3,4-Dichlorophenyl75 Pentyl 3,4-Dichlorophenyl 76 3-Methylbutyl 3,4-Dichlorophenyl 773-Methylbutyl 3,5-Dichlorophenyl 78 3-Methylbutyl 2,3-Dichlorophenyl 79Butyl 2,5-Dichlorophenyl 80 2-Methylpropyl 2,5-Dichlorophenyl 81 Pentyl2,5-Dichlorophenyl 82 3-Methylbutyl 2,5-Dichlorophenyl 83 Butyl2,4-Dichlorophenyl 84 2-Methylpropyl 2,4-Dichlorophenyl 85 3-Methylbutyl2,4-Dichlorophenyl 86 Allyl 3-Chlorophenyl 87 Propyl 3-Chlorophenyl 88Propyl 2,3,6-Trifluorophenyl 89 Methyl 5-Chloro-2-methoxyphenyl 90 Ethyl5-Chloro-2-methoxyphenyl 91 Allyl 5-Chloro-2-methoxyphenyl 92 Methyl2,5-Dichlorophenyl 93 Methyl 3-Bromophenyl 94 Ethyl 3-Bromophenyl 95Propyl 3-Bromophenyl 96 Methyl 3-Bromo-4-fluorophenyl 97 Methyl3-Iodophenyl 98 3-Methylbutyl 3-(2-{[(2-Methoxyphenyl) methyl]amino}ethoxy)phenyl 99 2-Methylpropyl 3-(2-{[(3-Methoxyphenyl) methyl]amino}ethoxy)phenyl 100 2-Methylpropyl 3-(2-{[(4-Methoxyphenyl) methyl]amino}ethoxy)phenyl 101 2-Methylpropyl 3-(2-{[(2-Chlorophenyl) methyl]amino}ethoxy)phenyl 102 Benzyl 2,5-Dimethoxyphenyl 103 2-Fluorobenzyl2,5-Dimethoxyphenyl 104 4-Fluorobenzyl 2,5-Dimethoxyphenyl 105 Butyl4-Pentylphenyl 106 2-Methylpropyl 4-Pentylphenyl 107 3-Methylbutyl4-Pentylphenyl 108 Butyl 3-Bromophenyl 109 2-Methylpropyl 3-Bromophenyl110 Pentyl 3-Bromophenyl 111 3-Methylbutyl 3-Bromophenyl 1122-Methylpropyl 4-Bromophenyl 113 3-Methylbutyl 4-Bromophenyl 114 Butyl2-Bromophenyl 115 Pentyl 2-Bromophenyl 116 3-Methylbutyl 2-Bromophenyl117 Ethyl 3-Iodophenyl 118 Allyl 3-Iodophenyl 119 Propyl3-Chloro-4-methylphenyl 120 Propyl 5-Bromo-2-thienyl 121 Ethyl Phenyl122 Allyl Phenyl 123 Propyl Phenyl 124 Allyl 3-Methylphenyl 125 Propyl3-Methylphenyl 126 Propyl 4-Methylphenyl 127 Methyl 3-Fluorophenyl 128Propyl 3-Fluorophenyl 129 Butyl 3-Chloro-4-methoxyphenyl 1302-Methylpropyl 3-Chloro-4-methoxyphenyl 131 3-Methylbutyl3-Chloro-4-methoxyphenyl 132 Butyl 5-Chloro-2-methoxyphenyl 1332-Methylpropyl 5-Chloro-2-methoxyphenyl 134 Pentyl5-Chloro-2-methoxyphenyl 135 3-Methylbutyl 5-Chloro-2-methoxyphenyl 136Butyl 3-Trifluoromethylphenyl 137 Pentyl 3-Trifluoromethylphenyl 1383-Methylbutyl 3-Trifluoromethylphenyl 139 3-Methylbutyl2-Trifluoromethylphenyl 140 Butyl 3,4-Dichlorophenyl 141 Propyl4-Fluorophenyl 142 Methyl 2-Fluorophenyl 143 Allyl 2-Fluorophenyl 144Propyl 2-Fluorophenyl 145 Propyl 3-Fluoro-4-methylphenyl 146 Methyl5-Fluoro-2-methylphenyl 147 Propyl 5-Fluoro-2-methylphenyl 148 Methyl3-Chlorophenyl 149 Allyl 3-Chlorophenyl 150 Propyl 3-Chlorophenyl 1513-Methylbutyl 4-Hexylphenyl 152 3-Methylbutyl 2-Fluoro-3-trifluoromethylphenyl 153 Butyl 2,5-Dichlorophenyl 154 2-Methylpropyl2,5-Dichlorophenyl 155 Pentyl 2,5-Dichlorophenyl 156 3-Methylbutyl2,5-Dichlorophenyl 157 Butyl 2,4-Dichlorophenyl 158 2-Methylpropyl2,4-Dichlorophenyl 159 3-Methylbutyl 2,4-Dichlorophenyl 160 Butyl4-Pentylphenyl 161 2-Methylpropyl 4-Pentylphenyl 162 3-Methylbutyl4-Pentylphenyl 163 Butyl 3-Bromophenyl 164 2-Methylpropyl 3-Bromophenyl165 2-Methylpropyl 3-Bromo-4-methylphenyl 166 3-Methylbutyl3-Bromo-4-methylphenyl 167 Butyl 3-Bromo-4-fluorophenyl 1682-Methylpropyl 3-Bromo-4-fluorophenyl 169 3-Methylbutyl3-Bromo-4-fluorophenyl 170 Butyl 3-Iodophenyl 171 2-Methylpropyl3-Iodophenyl 172 Pentyl 3-Iodophenyl 173 3-Methylbutyl 3-Iodophenyl 1742-Methylpropyl 4-Iodophenyl 175 3-Methylbutyl 3-Iodo-4-methylphenyl 176Butyl 2-Thienyl 177 Pentyl 2-Thienyl 178 3-Methylbutyl 2-Thienyl 179Butyl 3-Thienyl 180 Pentyl 3-Thienyl 181 3-Methylbutyl 3-Thienyl 1823-Methylbutyl Benzyl 183 Butyl 3-Methyl-2-thienyl 184 Pentyl3-Methyl-2-thienyl 185 3-Methylbutyl 3-Methyl-2-thienyl 186 Pentyl3-Methyl-5-thienyl 187 3-Methylbutyl 3-Methyl-5-thienyl 1883-Methylbutyl 3-Methylphenyl 189 2-Methylpropyl 5-Chloro-2-methoxyphenyl190 Pentyl 5-Chloro-2-methoxyphenyl 191 3-Methylbutyl5-Chloro-2-methoxyphenyl 192 Butyl 3-Trifluoromethylphenyl 193 Pentyl3-Trifluoromethylphenyl 194 3-Methylbutyl 3-Trifluoromethylphenyl 1953-Methylbutyl 2-Trifluoromethylphenyl 196 Butyl 3,4-Dichlorophenyl 1972-Methylpropyl 3,4-Dichlorophenyl 198 3-Methylbutyl 3,4-Dichlorophenyl199 3-Methylbutyl 3,5-Dichlorophenyl 200 3-Methylbutyl2,3-Dichlorophenyl 201 Butyl Phenyl 202 Pentyl Phenyl 203 3-MethylbutylPhenyl 204 Pentyl 3-Methylphenyl 205 3-Methylbutyl 3-Methylphenyl 2062-Methylpropyl 4-Methylphenyl 207 3-Methylbutyl 4-Methylphenyl 208Pentyl 2-Methylphenyl 209 3-Methylbutyl 2-Methylphenyl 210 Butyl3-Fluorophenyl 211 2-Methylpropyl 3-Fluorophenyl 212 Pentyl3-Fluorophenyl 213 3-Methylbutyl 3-Fluorophenyl 214 Pentyl4-Fluorophenyl 215 3-Methylbutyl 4-Fluorophenyl 216 Pentyl2-Fluorophenyl 217 3-Methylbutyl 2-Fluorophenyl 218 2-Methylpropyl3,4-Dimethylphenyl 219 3-Methylbutyl 3,4-Dimethylphenyl 220 Pentyl2,5-Dimethylphenyl 221 3-Methylbutyl 2,5-Dimethylphenyl 2222-Methylpropyl 2,4-Dimethylphenyl 223 3-Methylbutyl 2,4-Dimethylphenyl224 2-Methylpropyl 3-Methoxyphenyl 225 Pentyl 3-Methoxyphenyl 2263-Methylbutyl 3-Methoxyphenyl 227 2-Methylpropyl 4-Methoxyphenyl 2283-Methylbutyl 4-Methoxyphenyl 229 Pentyl 2-Methoxyphenyl 2303-Methylbutyl 2-Methoxyphenyl 231 2-Methylpropyl 3-Fluoro-4-methylphenyl232 Pentyl 3-Fluoro-4-methylphenyl 233 3-Methylbutyl3-Fluoro-4-methylphenyl 234 3-Methylbutyl 3-Fluoro-2-methylphenyl 2352-Methylpropyl 5-Fluoro-2-methylphenyl 236 Pentyl5-Fluoro-2-methylphenyl 237 2-Methylpropyl 3-Chloro-4-fluorophenyl 238Pentyl 3-Chloro-4-fluorophenyl 239 3-Methylbutyl 3-Chloro-4-fluorophenyl240 3-Methylbutyl 3,4,5-Trifluorophenyl 241 3-Methylbutyl 4-Butylphenyl242 Pentyl 4-i-propylphenyl 243 3-Methylbutyl 4-i-propylphenyl 244 Butyl4-Ethylthiophenyl 245 2-Methylpropyl 4-Ethylthiophenyl 246 3-Methylbutyl4-Ethylthiophenyl 247 3-Methylbutyl 3-Chloro-4-methoxyphenyl 248 Butyl5-Chloro-2-methoxyphenyl 249 3-Methylbutyl 5-Fluoro-2-methylphenyl 2502-Methylpropyl 2-Fluoro-3-methylphenyl 251 Pentyl2-Fluoro-3-methylphenyl 252 3-Methylbutyl 2-Fluoro-3-methylphenyl 2532-Methylpropyl 3-Chlorophenyl 254 Pentyl 3-Chlorophenyl 2553-Methylbutyl 3-Chlorophenyl 256 2-Methylpropyl 4-Chlorophenyl 2573-Methylbutyl 4-Chlorophenyl 258 3-Methylbutyl 2-Chlorophenyl 2593-Methylbutyl 3,4-Difluorophenyl 260 3-Methylbutyl 1,2-Difluorophenyl261 Pentyl 2,5-Difluorophenyl 262 3-Methylbutyl 2,5-Difluorophenyl 263Pentyl 2,4-Difluorophenyl 264 3-Methylbutyl 2,4-Difluorophenyl 2653-Methylbutyl 4-Propylphenyl 266 Pentyl 1,3-Benzodioxol-5-yl 2673-Methylbutyl 1,3-Benzodioxol-5-yl 268 3-Methylbutyl 4-Methylthiophenyl269 3-Methylbutyl 3-Fluoro-4-methoxyphenyl 270 2-Methylpropyl4-Chloro-3-methylphenyl 271 3-Methylbutyl 4-Chloro-3-methylphenyl 272Butyl 3-Chloro-4-fluorophenyl

EXAMPLE 6

For each compound, the definitions of R₂ and R₃ are specified in thefollowing table.

Compound No. R₂ R₃ 273 2-Methylpropyl 2,4,6-Trifluorophenyl 2743-Methylbutyl 2,4,6-Trifluorophenyl 275 2-Methylpropyl2,3,6-Trifluorophenyl 276 Pentyl 2,3,6-Trifluorophenyl 277 3-Methylbutyl2,3,6-Trifluorophenyl 278 Pentyl 2-Chloro-6-fluorophenyl 2793-Methylbutyl 2-Chloro-6-fluorophenyl 280 Pentyl 2-Fluoro-6-trifluoromethylphenyl 281 3-Methylbutyl 2-Fluoro-6-trifluoromethylphenyl 282 Pentyl 3-Bromo-4-fluorophenyl 2832-Methylpropyl 4-Hexylphenyl 284 Butyl 4-Pentoxyphenyl 2852-Methylpropyl 4-Pentoxyphenyl 286 Butyl 2-Fluoro-3-trifluoromethylphenyl 287 2-Methylpropyl 2-Fluoro-3-trifluoromethylphenyl 288 3-Methylbutyl 3-Bromo-4-fluorophenyl 2892-Methylpropyl 4-heptylphenyl 290 Butyl 3-Iodophenyl 291 2-Methylpropyl3-Iodophenyl 292 Pentyl 3-Iodophenyl 293 3-Methylbutyl 3-Iodophenyl 294Butyl 4-Iodophenyl 295 2-Methylpropyl 4-Iodophenyl 296 2-Methylpropyl4-Pentylphenyl 297 3-Methylbutyl 2-Fluoro-3- trifluoromethylphenyl 298Butyl 3-Bromo-4-methylphenyl 299 2-Methylpropyl 3-Bromo-4-methylphenyl300 Pentyl 3-Bromo-4-methylphenyl 301 3-Methylbutyl3-Bromo-4-methylphenyl 302 Butyl 3-Bromo-4-fluorophenyl 3032-Methylpropyl 3-Bromo-4-fluorophenyl 304 3-Methylbutyl3,4-Dichlorophenyl 305 Butyl 2,3-Dichlorophenyl 306 2-Methylpropyl2,3-Dichlorophenyl 307 3-Methylbutyl 2,3-Dichlorophenyl 308 Butyl2,5-Dichlorophenyl 309 Butyl 3-Bromophenyl 310 2-Methylpropyl3-Bromophenyl 311 Pentyl 3-Bromophenyl 312 3-Methylbutyl 3-Bromophenyl313 Butyl 4-Bromophenyl 314 2-Methylpropyl 4-Bromophenyl 3153-Methylbutyl 4-Bromophenyl 316 Butyl 2-Bromophenyl 317 Pentyl2-Bromophenyl 318 3-Methylbutyl 2-Bromophenyl 319 Pentyl 4-Hexylphenyl320 2-Methylpropyl 4-Chloro-2-methoxyphenyl 321 2-Methylpropyl2,5-Dichlorophenyl 322 Pentyl 2,5-Dichlorophenyl 323 3-Methylbutyl2,5-Dichlorophenyl 324 Butyl 2,4-Dichlorophenyl 325 2-Methylpropyl2,4-Dichlorophenyl 326 Pentyl 2,4-Dichlorophenyl 327 3-Methylbutyl2,4-Dichlorophenyl 328 2-Methylpropyl 2,5-Dimethoxyphenyl 329 Pentyl2,5-Dimethoxyphenyl 330 3-Methylbutyl 2,5-Dimethoxyphenyl 3312-Methylpropyl 2,4-Dimethoxyphenyl 332 3-Methylbutyl 2,4-Dimethoxyphenyl333 Pentyl 4-Chloro-2-methoxyphenyl 334 3-Methylbutyl4-Chloro-2-methoxyphenyl 335 Butyl 3-Trifluoromethylphenyl 3362-Methylpropyl 3-Trifluoromethylphenyl 337 Pentyl3-Trifluoromethylphenyl 338 3-Methylbutyl 3-Trifluoromethylphenyl 3392-Methylpropyl 4-Trifluoromethylphenyl 340 Butyl 2-Trifluoromethylphenyl341 3-Methylbutyl 2-Trifluoromethylphenyl 342 Butyl 3,4-Dichlorophenyl343 2-Methylpropyl 3,4-Dichlorophenyl 344 Butyl 4-Methylthiophenyl 345Butyl 3-Chloro-4-methoxyphenyl 346 2-Methylpropyl3-Chloro-4-methoxyphenyl 347 3-Methylbutyl 3-Chloro-4-methoxyphenyl 348Butyl 5-Chloro-2-methoxyphenyl 349 2-Methylpropyl5-Chloro-2-methoxyphenyl 350 Pentyl 5-Chloro-2-methoxyphenyl 3513-Methylbutyl 5-Chloro-2-methoxyphenyl 352 Butyl 2,5-Difluorophenyl 3532-Methylpropyl 2,5-Difluorophenyl 354 Pentyl 2,5-Difluorophenyl 3553-Methylbutyl 2,5-Difluorophenyl 356 Butyl 2,4-Difluorophenyl 3572-Methylpropyl 4-Methylthiophenyl 358 Butyl 3-Fluoro-4-methoxyphenyl 3592-Methylpropyl 3-Fluoro-4-methoxyphenyl 360 3-Methylbutyl3-Fluoro-4-methoxyphenyl 361 2-Methylpropyl 4-Chloro-3-methylphenyl 362Butyl 3-Chloro-4-fluorophenyl 363 2-Methylpropyl 3-Chloro-4-fluorophenyl364 Pentyl 3-Chloro-4-fluorophenyl 365 3-Methylbutyl3-Chloro-4-fluorophenyl 366 2-Methylpropyl 4-Ethylthiophenyl 367 Butyl2,5-Dimethoxyphenyl 368 Butyl 2-Chlorophenyl 369 2-Methylpropyl2,4-Difluorophenyl 370 Pentyl 2,4-Difluorophenyl 371 3-Methylbutyl2,4-Difluorophenyl 372 Butyl 1,3-Benzodioxol-5-yl 373 2-Methylpropyl1,3-Benzodioxol-5-yl 374 Pentyl 1,3-Benzodioxol-5-yl 375 3-Methylbutyl1,3-Benzodioxol-5-yl 376 3-Methylbutyl 3-Fluoro-2-methylphenyl 377 Butyl5-Fluoro-2-methylphenyl 378 2-Methylpropyl 5-Fluoro-2-methylphenyl 379Pentyl 5-Fluoro-2-methylphenyl 380 3-Methylbutyl 5-Fluoro-2-methylphenyl381 2-Methylpropyl 2-Chlorophenyl 382 Pentyl 2-Chlorophenyl 3833-Methylbutyl 2-Chlorophenyl 384 Butyl 3,4-Difluorophenyl 3852-Methylpropyl 3,4-Difluorophenyl 386 Pentyl 3,4-Difluorophenyl 3873-Methylbutyl 3,4-Difluorophenyl 388 Butyl 2,3-Difluorophenyl 3892-Methylpropyl 2,3-Difluorophenyl 390 Pentyl 2,3-Difluorophenyl 3913-Methylbutyl 2,3-Difluorophenyl 392 2-Methylpropyl 4-Methoxyphenyl 393Butyl 3-Chlorophenyl 394 2-Methylpropyl 3-Chlorophenyl 395 Pentyl3-Chlorophenyl 396 3-Methylbutyl 3-Chlorophenyl 397 Butyl 4-Chlorophenyl398 2-Methylpropyl 4-Chlorophenyl 399 3-Methylbutyl 4-Chlorophenyl 400Butyl 2,5-Dimethylphenyl 401 2-Methylpropyl 2,5-Dimethylphenyl 402Pentyl 2,5-Dimethylphenyl 403 3-Methylbutyl 2,5-Dimethylphenyl 404 Butyl2,4-Dimethylphenyl 405 3-Methylbutyl 4-Methoxyphenyl 406 Butyl2-Methoxyphenyl 407 2-Methylpropyl 2-Methoxyphenyl 408 Pentyl2-Methoxyphenyl 409 3-Methylbutyl 2-Methoxyphenyl 410 Butyl3-Fluoro-4-methylphenyl 411 2-Methylpropyl 3-Fluoro-4-methylphenyl 412Pentyl 3-Fluoro-4-methylphenyl 413 3-Methylbutyl 3-Fluoro-4-methylphenyl414 Butyl 3-Fluoro-2-methylphenyl 415 2-Methylpropyl3-Fluoro-2-methylphenyl 416 Butyl 4-Fluorophenyl 417 2-Methylpropyl2,4-Dimethylphenyl 418 3-Methylbutyl 2,4-Dimethylphenyl 419 Butyl3-Methoxyphenyl 420 2-Methylpropyl 3-Methoxyphenyl 421 Pentyl3-Methoxyphenyl 422 3-Methylbutyl 3-Methoxyphenyl 423 Butyl4-Methoxyphenyl 424 3-Methylbutyl 3-Methylphenyl 425 Butyl4-Methylphenyl 426 2-Methylpropyl 4-Methylphenyl 427 Pentyl4-Methylphenyl 428 3-Methylbutyl 4-Methylphenyl 429 2-Methylpropyl4-Fluorophenyl 430 Pentyl 4-Fluorophenyl 431 3-Methylbutyl4-Fluorophenyl 432 Butyl 2-Fluorophenyl 433 2-Methylpropyl2-Fluorophenyl 434 Pentyl 2-Fluorophenyl 435 3-Methylbutyl2-Fluorophenyl 436 2-Methylpropyl 4-Ethylphenyl 437 Butyl3,4-Dimethylphenyl 438 2-Methylpropyl 3,4-Dimethylphenyl 4393-Methylbutyl 3,4-Dimethylphenyl 440 Butyl 2-Methylphenyl 441 Pentyl2-Methylphenyl 442 3-Methylbutyl 2-Methylphenyl 443 Butyl 3-Fluorophenyl444 2-Methylpropyl 3-Fluorophenyl 445 Pentyl 3-Fluorophenyl 4463-Methylbutyl 3-Fluorophenyl 447 Butyl Phenyl 448 2-Methylpropyl Phenyl449 Pentyl Phenyl 450 3-Methylbutyl Phenyl 451 Butyl 3-Methylphenyl 4522-Methylpropyl 3-Methylphenyl 453 Pentyl 3-Methylphenyl

EXAMPLE 7

For each compound, the definitions of R₂ and R₃ are specified in thefollowing table.

Compound No. R₂ R₃ 454 Allyl 2,5-Dichlorophenyl 455 Propyl2,5-Dichlorophenyl 456 Propyl 2,4-Dichlorophenyl 457 Propyl4-Pentylphenyl 458 Allyl 3-Bromophenyl 459 Propyl 3-Bromophenyl 460Propyl 4-Bromophenyl 461 Propyl 2-Chlorophenyl 462 Methyl Phenyl 463Propyl Phenyl 464 Methyl 3-Methylphenyl 465 Propyl 3-Methylphenyl 466Propyl 2-Chlorophenyl 467 Propyl 3,4-Difluorophenyl 468 Methyl2,3-Difluorophenyl 469 Propyl 2,3-Difluorophenyl 470 Methyl2,5-Difluorophenyl 471 Allyl 2,5-Difluorophenyl 472 Propyl2,5-Difluorophenyl 473 Propyl 2,4-Difluorophenyl 474 Allyl1,3-Benzodioxol-5-yl 475 Propyl 1,3-Benzodioxol-5-yl 476 Propyl4-Methylthiophenyl 477 Propyl 4-Chloro-3-methylphenyl 478 Propyl4-Methylphenyl 479 Propyl 3-Fluorophenyl 480 Propyl 4-Fluorophenyl 481Methyl 2-Fluorophenyl 482 Allyl 2-Fluorophenyl 483 Propyl 2-Fluorophenyl484 Propyl 3,4-Dimethylphenyl 485 Propyl 3-Fluoro-4-methylphenyl 486Propyl 2-Fluoro-3-methylphenyl 487 Allyl 3-Chlorophenyl 488 Propyl3-Chlorophenyl 489 Propyl 4-Chlorophenyl 490 2-Methylpropyl3-Chloro-2-thienyl 491 Pentyl 3-Chloro-2-thienyl 492 3-Methylbutyl3-Chloro-2-thienyl 493 Butyl 3-Ethoxy-2-thienyl 494 Pentyl3-Ethoxy-2-thienyl 495 3-Methylbutyl 2-Methoxybenzyl 496 3-Methylbutyl2-(2-Fluorophenyl) ethenyl 497 2-Methylpropyl 2-(2-Chlorophenyl) ethenyl498 3-Methylbutyl 2-(2-Chlorophenyl) ethenyl 499 Pentyl 2-Fluoro-6-trifluoromethylphenyl 500 3-Methylbutyl 3-Ethoxy-2-thienyl 501 Butyl5-Methylthio-2-thienyl 502 2-Methylpropyl 5-Methylthio-2-thienyl 5033-Methylbutyl 5-Methylthio-2-thienyl 504 3-Methylbutyl 4-Fluorophenyl505 3-Methylbutyl 2-Fluorophenyl 506 3-Methylbutyl 3-Methoxyphenyl 5073-Methylbutyl 2,3,5,6-Tetrafluoro phenyl 508 2-Methylpropyl2,4,6-Trifluorophenyl 509 3-Methylbutyl 2,4,6-Trifluorophenyl 510 Butyl2,3,6-Trifluorophenyl 511 2-Methylpropyl 2,3,6-Trifluorophenyl 5123-Methylbutyl 2-Fluoro-6- trifluoromethylphenyl 513 2-Methylpropyl2,4,6-Trichlorophenyl 514 Pentyl 2,5-Dimethyl-3-furyl 515 3-Methylbutyl4,5-Dimethyl-2-furyl 516 Butyl 3,4-Dimethyl-2-furyl 517 2-Methylpropyl3,4-Dimethyl-2-furyl 518 Pentyl 3,4-Dimethyl-2-furyl 519 3-Methylbutyl3,4-Dimethyl-2-furyl 520 Butyl 4-Methoxy-3-thienyl 521 3-Methylbutyl4-Methoxy-3-thienyl 522 Butyl 3-Chloro-2-thienyl 523 Allyl3-Bromo-4-fluorophenyl 524 Propyl 3-Bromo-4-fluorophenyl 525 Methyl3-Iodophenyl 526 Ethyl 3-Iodophenyl 527 Allyl 3-Iodophenyl 528 Propyl3-Iodophenyl 529 Propyl 3-Methyl-2-thienyl 530 Propyl 3-Fluorobenzyl 531Pentyl 2,3,6-Trifluorophenyl 532 3-Methylbutyl 2,3,6-Trifluorophenyl 533Butyl 2-Chloro-6-fluorophenyl 534 2-Methylpropyl 2-Chloro-6-fluorophenyl535 Pentyl 2-Chloro-6-fluorophenyl 536 3-Methylbutyl2-Chloro-6-fluorophenyl 537 Butyl 2-Fluoro-6- trifluoromethylphenyl 5383-Methylbutyl 3-Chlorobenzyl 539 2-Methylpropyl 4-Chlorobenzyl 5403-Methylbutyl 2-Chlorobenzyl 541 Butyl 2,3,5,6-Tetrafluoro phenyl 5422-Methylpropyl 2,3,5,6-Tetrafluoro phenyl 543 Pentyl 2,3,5,6-Tetrafluorophenyl 544 Allyl 3-Chloro-4-fluorophenyl 545 Propyl3-Chloro-4-fluorophenyl 546 Propyl 4-Butylphenyl 547 Propyl3-Chloro-4-methoxyphenyl 548 Allyl 5-Chloro-2-methoxyphenyl 549 Propyl5-Chloro-2-methoxyphenyl 550 Propyl 3,4-Dichlorophenyl 551 Propyl4-Hexylphenyl 552 Methyl 3-Bromo-4-methylphenyl 553 Allyl3-Bromo-4-methylphenyl 554 Propyl 3-Bromo-4-methylphenyl 555 Methyl3-Bromo-4-fluorophenyl 556 Butyl 2-Methoxybenzyl

EXAMPLE 8

For each compound, the definitions of R₂ and R₃ are specified in thefollowing table.

Compound No. R₂ R₃ 557 Propyl 3-Chlorophenyl 558 Propyl Phenyl 559 Allyl2-Fluorophenyl 560 Propyl 2-Fluorophenyl 561 Propyl 3-Fluoro-4-methylphenyl 562 Methyl 2,5-Dichlorophenyl 563 Propyl 2,5-Dichlorophenyl564 Propyl 4-Pentylphenyl 565 Propyl 3-Bromophenyl 566 Propyl3-Methyl-2-thienylCompound No. 567:(5-Chloro-2-methoxyphenyl)-N-({3-[(2-chlorophenyl)methyl]imidazolo[5,4-b]pyridin-2-yl}methyl-N-pentylcarboxamide.

EXAMPLE 9

For each compound, the definitions of R₂ and R₃ are specified in thefollowing table.

Compound No. R₂ R₃ 568 Methyl Phenyl 569 Methyl 3-Chlorophenyl 570 Butyl2,5-Dimethylphenyl 571 Butyl 5-Fluoro-2-methylphenyl 572 Butyl2,3-Dimethylphenyl 573 Propyl 3-Fluorophenyl 574 Butyl 3-Methylphenyl575 Butyl 4-Fluorophenyl 576 Butyl 3-Methoxyphenyl 577 Butyl2,5-Difluorophenyl 578 Methyl 2-Fluorophenyl 579 Butyl 4-Methylphenyl580 Butyl 2-Fluorophenyl 581 Butyl 4-Methoxyphenyl 582 Butyl3-Chlorophenyl 583 Methyl 2,5-Dimethylphenyl 584 Butyl 2-Methylphenyl585 Butyl 4-Ethylphenyl 586 Butyl 2-Methoxyphenyl 587 Butyl3-Chlorophenyl 588 Propyl 3-Fluoro-4-methylphenyl 589 Butyl3-Fluorophenyl 590 Butyl 3,4-Dimethylphenyl 591 Butyl3-Fluoro-4-methylphenyl 592 Butyl 3,4-Difluorophenyl 593 Propyl2,4-Dimethoxyphenyl 594 Methyl 2,5-Dichlorophenyl 595 Butyl5-Chloro-2-methoxyphenyl 596 Butyl 3-Methyl-2-thienyl 597 Butyl3-Methylphenyl 598 Pentyl 3-Fluorophenyl 599 Pentyl 2,5-Dimethylphenyl600 Propyl 2,5-Dichlorophenyl 601 Butyl 3-Methyl-2-thienyl 602 Pentyl3-Methylphenyl 603 Butyl 2-Fluorophenyl 604 Pentyl 3-Methoxyphenyl 605Methyl 3-Bromophenyl 606 Butyl 3-Iodophenyl 607 Butyl 4-Fluorophenyl 6082-Methylpropyl 4-Methylphenyl 609 2-Methylpropyl 2-Fluorophenyl 6102-Methylpropyl 4-Methoxyphenyl 611 Propyl 3-Bromophenyl 612 Allyl4-Octylphenyl 613 Butyl Phenyl 614 Pentyl 2-Methylphenyl 615 Pentyl2-Fluorophenyl 616 Butyl 2-Methoxyphenyl 617 Butyl3-Chloro-4-methoxyphenyl 618 Propyl 4-Octylphenyl 619 Pentyl Phenyl 620Butyl 3-Fluorophenyl 621 2-Methylpropyl 3,4-Dimethylphenyl 622 Pentyl2-Methoxyphenyl 623 Butyl 3-Fluoro-4-methylphenyl 624 Butyl2-Fluoro-3-methylphenyl 625 2-Methylpropyl 4-Chlorophenyl 6262-Methylpropyl 2,3-Difluorophenyl 627 2-Methylpropyl1,3-Benzodioxol-5-yl 628 2-Methylpropyl 3-Chloro-4-methoxyphenyl 6292-Methylpropyl 3-Fluoro-4-methylphenyl 630 Pentyl2-Fluoro-3-methylphenyl 631 Pentyl 2-Chlorophenyl 632 Pentyl2,3-Difluorophenyl 633 Butyl 4-Methylthiophenyl 634 2-Methylpropyl3-Chloro-4-methoxyphenyl 635 Butyl 5-Fluoro-2-methylphenyl 636 Butyl3-Chlorophenyl 637 Butyl 3,4-Difluorophenyl 638 Butyl 2,5-Difluorophenyl639 Butyl 3-Chloro-4-fluorophenyl 640 Butyl 5-Chloro-2-methoxyphenyl 6412-Methylpropyl 5-Fluoro-2-methylphenyl 642 2-Methylpropyl 3-Chlorophenyl643 2-Methylpropyl 3,4-Difluorophenyl 644 Pentyl 2,5-Difluorophenyl 6452-Methylpropyl 4-Ethylthiophenyl 646 2-Methylpropyl5-Chloro-2-methoxyphenyl 647 Pentyl 5-Fluoro-2-methylphenyl 648 Pentyl3-Chlorophenyl 649 Butyl 2,3-Difluorophenyl 650 2-Methylpropyl2,4-Difluorophenyl 651 Butyl 3-Chloro-4-methoxyphenyl 652 Pentyl5-Chloro-2-methoxyphenyl 653 3-Methylbutyl 5-Chloro-2-methoxyphenyl 6543-Methylbutyl 2,5-Dichlorophenyl 655 2-Methylpropyl 4-Bromophenyl 656Butyl 2-Thienyl 657 3-Methylbutyl 3-Thienyl 658 2-Methylpropyl3-Methyl-2-thienyl 659 3-Methylbutyl 3-Trifluoromethylphenyl 660 Butyl3-Bromophenyl 661 3-Methylbutyl 2-Bromophenyl 662 Pentyl 2-Thienyl 663Butyl 5-Methyl-2-thienyl 664 3-Methylbutyl 3-Methyl-2-thienyl 6652-Methylpropyl 3,4-Dichlorophenyl 666 2-Methylpropyl 3-Bromophenyl 6673-Methylbutyl 3-Bromo-4-fluorophenyl 668 3-Methylbutyl 2-Thienyl 669Pentyl 5-Methyl-2-thienyl 670 Butyl 3-Fluorophenyl 671 Butyl2,5-Dichlorophenyl 672 Pentyl 3-Bromophenyl 673 Pentyl 3-Iodophenyl 674Butyl 3-Thienyl 675 3-Methylbutyl 5-Methyl-2-thienyl 676 3-Methylbutyl3-Fluorophenyl 677 Pentyl 2,5-Dichlorophenyl 678 3-Methylbutyl3-Bromophenyl 679 3-Methylbutyl 3-Iodophenyl 680 Pentyl 3-Thienyl 681Butyl 3-Methyl-2-thienyl 682 2-Methylpropyl 2-Chlorophenyl 8152-Methylpropyl 3,5-Difluorophenyl 816 3-Methylbutyl 3,5-Difluorophenyl817 Butyl 3,5-Difluorophenyl 2238 Benzyl 3-Fluorophenyl 2242 Benzyl2-Fluorophenyl 2253 Benzyl 2-Methoxyphenyl 2257 Benzyl5-Fluoro-2-methylphenyl 2260 Benzyl 3-Chlorophenyl 2268 Benzyl2,3-Difluorophenyl 2271 Benzyl 2,5-Difluorophenyl

EXAMPLE 10

For each compound, the definitions of R₂ and R₃ are specified in thefollowing table.

Compound No. R₂ R₃ 683 Allyl 3-Fluorophenyl 684 Allyl 3,4-Difluorophenyl685 Propyl 1,3-Benzodioxol-5-yl 686 Allyl 5-Chloro-2-methoxyphenyl 687Propyl 3-Methyl-2-Thienyl 688 Propyl 3-Fluoro-4-methylphenyl 689 Propyl3-Fluorophenyl 690 Propyl 3,4-Difluorophenyl 691 Allyl3-Chloro-4-fluorophenyl 692 Propyl 5-Chloro-2-methoxyphenyl 693 AllylPhenyl 694 Allyl 5-Fluoro-2-methylphenyl 695 Propyl 4-Fluorophenyl 696Allyl 2,5-Difluorophenyl 697 Propyl 3-Chloro-4-fluorophenyl 698 Methyl2,5-Dichlorophenyl 699 Propyl Phenyl 700 Propyl 5-Fluoro-2-methylphenyl701 Allyl 2-Fluorophenyl 702 Propyl 2,5-Difluorophenyl 703 Methyl5-Chloro-2-methoxyphenyl 704 Allyl 2,5-Dichlorophenyl 705 Allyl3-Methylphenyl 706 Allyl 3-Chlorophenyl 707 Propyl 2-Fluorophenyl 708Allyl 1,3-Benzodioxol-5-yl 709 Ethyl 5-Chloro-2-methoxyphenyl 710 Propyl2,5-Dichlorophenyl 711 Propyl 3-Methylphenyl 712 Propyl 3-Chlorophenyl713 Propyl 4-Methylthiophenyl 714 Propyl 3-Iodo-4-methylphenyl 887Propyl 2,3,6-Trifluorophenyl 2306 3-Methylbutyl 2,3,6-Trifluorophenyl2347 3-Methylbutyl 3-(2-1,2,3,4-Teterahydro isoquinolinyl methyl) phenyl2348 3-Methylbutyl 3-(Diethylamino methyl)phenyl 2349 3-Methylbutyl3-(Hexylmethyl amino methyl)phenyl 2351 3-Methylbutyl 3-(Dibutylaminomethyl)phenyl 2364 3-Methylbutyl 3-[(1-methylethyl) methylaminomethyl]phenyl 2365 3-Methylbutyl 3-(Cyclohexyl ethylamino methyl)phenyl2367 3-Methylbutyl 3-[bis(2-Methoxyethyl) aminomethyl] phenyl 23693-Methylbutyl 3-[(3,3,5-Trimethylaza perhydroepinyl)methyl]phenyl

EXAMPLE 11

For each compound, the definitions of R₂ and R₃ are specified in thefollowing table.

Compound No. R₂ R₃ 715 Methyl 3-Fluorophenyl 716 Methyl 5-Fluoro2-methylphenyl 717 Methyl 3-Chlorophenyl 718 Methyl5-Chloro-2-methoxyphenyl 839 2-Methylpropyl 2,3,6-Trifluorophenyl 840Pentyl 2,3,6-Trifluorophenyl 841 3-Methylbutyl 2,3,6-Trifluorophenyl 938Butyl Phenyl 939 2-Methylpropyl Phenyl 940 Pentyl Phenyl 9413-Methylbutyl Phenyl 942 Butyl 3-Methylphenyl 943 2-Methylpropyl3-Methylphenyl 944 3-Methylbutyl 3-Methylphenyl 945 2-Methylpropyl4-Methylphenyl 946 Butyl 3-Fluorophenyl 947 Pentyl 3-Fluorophenyl 9483-Methylbutyl 3-Fluorophenyl 949 3-Methylbutyl 4-Fluorophenyl 950 Butyl2-Fluorophenyl 951 2-Methylpropyl 2-Fluorophenyl 952 Pentyl2-Fluorophenyl 953 3-Methylbutyl 2-Fluorophenyl 954 2-Methylpropyl3,4-Dimethylphenyl 1002 Butyl 2-Chlorophenyl 1003 Pentyl 2-Chlorophenyl1004 3-Methylbutyl 2-Chlorophenyl 1005 Butyl 3,4-Difluorophenyl 10062-Methylpropyl 3,4-Difluorophenyl 1007 Pentyl 3,4-Difluorophenyl 10083-Methylbutyl 3,4-Difluorophenyl 1009 Butyl 2,3-Difluorophenyl 10102-Methylpropyl 2,3-Difluorophenyl 1011 Pentyl 2,3-Difluorophenyl 10123-Methylbutyl 2,3-Difluorophenyl 1013 Butyl 2,5-Difluorophenyl 10142-Methylpropyl 2,5-Difluorophenyl 1015 Pentyl 2,5-Difluorophenyl 10163-Methylbutyl 2,5-Difluorophenyl 1017 Butyl 2,4-Difluorophenyl 10182-Methylpropyl 2,4-Difluorophenyl 1019 3-Methylbutyl 2,4-Difluorophenyl1020 2-Methylpropyl 3-Ethoxyphenyl 1021 Butyl 1,3-Benzodioxol-5-yl 10222-Methylpropyl 1,3-Benzodioxol-5-yl 1023 3-Methylbutyl1,3-Benzodioxol-5-yl 1024 2-Methylpropyl 4-Methylthiophenyl 10253-Methylbutyl 4-Methylthiophenyl 1026 2-Methylpropyl3-Fluoro-4-methoxyphenyl 1027 3-Methylbutyl 3-Fluoro-4-methoxyphenyl1028 2-Methylpropyl 4-Chloro-3-methylphenyl 1029 Butyl3-Chloro-4-fluorophenyl 1030 2-Methylpropyl 3-Chloro-4-fluorophenyl 1031Pentyl 3-Chloro-4-fluorophenyl 1032 3-Methylbutyl3-Chloro-4-fluorophenyl 1033 2-Methylpropyl 3,4,5-Trifluorophenyl 10343-Methylbutyl 3,4,5-Trifluorophenyl 1035 2-Methylpropyl 4-Butylphenyl1036 2-Methylpropyl 4-Ethylthiophenyl 1109 Cyclopropyl Phenyl methyl1110 Cyclopropyl 3-Methylphenyl Methyl 1111 Cyclopropyl 4-MethylphenylMethyl 1112 Cyclopropyl 3-Fluorophenyl Methyl 1113 Cyclopropyl2-Fluorophenyl Methyl 1114 Cyclopropyl 3-Methoxyphenyl Methyl 1115Cyclopropyl 3-Fluoro-4-methylphenyl Methyl 1116 Cyclopropyl5-Fluoro-2-methylphenyl methyl 1130 Cyclopropyl 5-Chloro-2-methoxyphenylMethyl 1131 Cyclopropyl 2,5-Dichlorophenyl Methyl 1132 Cyclopropyl3-Bromophenyl Methyl 1133 3-Methylbutyl 5-Chloro-2-methoxyphenyl 1134Butyl 2,5-Dichlorophenyl 1135 2-Methylpropyl 2,5-Dichlorophenyl 1136Pentyl 2,5-Dichlorophenyl 1137 3-Methylbutyl 2,5-Dichlorophenyl 11382-Methylpropyl 2,4-Dichlorophenyl 1139 2-Methylpropyl 4-Pentylphenyl1140 Butyl 3-Bromophenyl 1141 2-Methylpropyl 3-Bromophenyl 1142 Pentyl3-Bromophenyl 1143 3-Methylbutyl 3-Bromophenyl 1144 2-Methylpropyl4-Bromophenyl 1256 Cyclopropyl 3,4-Difluorophenyl Methyl 1257Cyclopropyl 2,4-Difluorophenyl Methyl 1258 Propyl 1,3-Benzodioxol-5-yl1259 Cyclopropyl 1,3-Benzodioxol-5-yl Methyl 1260 Cyclopropyl3-Chloro-4-fluorophenyl Methyl 1261 3-Methylbutyl 3-Iodo-4-methylphenyl1262 3-Methylbutyl 2-Thienyl 1263 3-Methylbutyl 3-Thienyl 12642-Methylpropyl 5-Methyl-2-thienyl 1265 Pentyl 5-Methyl-2-thienyl 12663-Methylbutyl 5-Methyl-2-thienyl 1267 3-Methylbutyl 3-Fluorobenzyl 1448Methyl 2,5-Difluorophenyl 1449 Methyl 2,5-Dichlorophenyl 20053-Methylbutyl 5-Bromo-2-thienyl 2239 Benzyl 3-Fluorophenyl 2243 Benzyl2-Fluorophenyl 2245 Benzyl 3,4-Dimethylphenyl 2251 Benzyl3-Methoxyphenyl 2254 Benzyl 2-Methoxyphenyl 2258 Benzyl5-Fluoro-2-methylphenyl 2261 Benzyl 3-Chlorophenyl 2266 Benzyl3,4-Difluorophenyl 2269 Benzyl 2,3-Difluorophenyl 2272 Benzyl2,5-Difluorophenyl 2281 Benzyl 5-Chloro-2-methoxyphenyl 2289 Benzyl2,5-Dichlorophenyl 2292 Benzyl 3-Bromophenyl 2295 Benzyl 2-Bromophenyl2298 Benzyl 3-Iodophenyl 2302 Benzyl 2,5-Dimethylpyrrol-3-yl 2305 Benzyl3-Methylbutyl 2320 3-Methylbutyl 3-(Methylamino methyl)phenyl 23213-Methylbutyl 3-(Ethylamino methyl)phenyl 2322 3-Methylbutyl3-(Cyclobutyl amino methyl)phenyl 2323 3-Methylbutyl 3-[(1-Methylpropyl)amino methyl]phenyl 2324 3-Methylbutyl 3-(Cyclopentyl aminomethyl)phenyl 2350 3-Methylbutyl 3-(Dibutylamino methyl)phenyl 23663-Methylbutyl 3-[bis(2-Methoxyethyl) aminomethyl] phenyl 23683-Methylbutyl 3-[(3,3,5-Trimethylaza perhydroepinyl)methyl]phenyl 2391Methyl 2,5-Difluorophenyl

EXAMPLE 12

For each compound, the definitions of R₂ and R₃ are specified in thefollowing table.

Compound No. R₂ R₃ 719 Propyl 3-Fluorophenyl 720 Propyl1,3-Benzodioxol-5-yl 721 Propyl 5-Fluoro-2-methylphenyl 722 Allyl2-Fluorophenyl 723 Propyl 3-Chloro-4-fluorophenyl 724 Propyl3-Chlorophenyl 725 Propyl 2-Fluorophenyl 726 Allyl5-Chloro-2-methoxyphenyl 727 Allyl 3-Chlorophenyl 728 Methyl3-Fluorophenyl 729 Methyl 2,5-Difluorophenyl 730 Propyl Phenyl 731Propyl 3-Chlorophenyl 732 Allyl 3-Fluorophenyl 733 Propyl2,5-Difluorophenyl 734 Propyl 3-Fluoro-4-methylphenyl 735 Propyl4-Methylthio phenyl 736 3-Methylbutyl 3-Fluorophenyl 737 2-Methylpropyl2-Fluorophenyl 738 Butyl 3,4-Difluorophenyl 739 2-Methylpropyl2,5-Difluorophenyl 740 3-Methylbutyl 1,3-Benzodioxol-5-yl 741 Butyl4-Fluorophenyl 742 Pentyl 2-Fluorophenyl 743 2-Methylpropyl3,4-Difluorophenyl 744 Pentyl 2,5-Difluorophenyl 745 Butyl3-Chloro-4-fluorophenyl 746 Butyl 3-Fluorophenyl 747 2-Methylpropyl4-Fluorophenyl 748 3-Methylbutyl 2-Fluorophenyl 749 Pentyl3,4-Difluorophenyl 750 3-Methylbutyl 2,5-Difluorophenyl 7512-Methylpropyl 3-Chloro-4-fluorophenyl 752 2-Methylpropyl 3-Fluorophenyl753 3-Methylbutyl 4-Fluorophenyl 754 2-Methylpropyl 2,5-Dimethylphenyl755 3-Methylbutyl 3,4-Difluorophenyl 756 Butyl 1,3-Benzodioxol-5-yl 757Pentyl 3-Chloro-4-fluorophenyl 758 Pentyl 3-Fluorophenyl 759 Butyl2-Fluorophenyl 760 3-Methylbutyl 2,5-Dimethylphenyl 761 Butyl2,5-Difluorophenyl 762 2-Methylpropyl 1,3-Benzodioxol-5-yl 7633-Methylbutyl 3-Chloro-4-fluorophenyl 764 Butyl 5-Chloro-2-methoxyphenyl765 2-Methylpropyl 2,5-Dichlorophenyl 766 Pentyl 5-Methyl-2-thienyl 7673-Methylbutyl Phenyl 768 2-Methylpropyl 2-Methylphenyl 769 3-Methylbutyl5-Fluoro-2-methylphenyl 770 2-Methylpropyl 5-Chloro-2-methoxyphenyl 771Pentyl 2,5-Dichlorophenyl 772 3-Methylbutyl 5-Methyl-2-thienyl 773 Butyl3-Methylphenyl 774 3-Methylbutyl 2-Methylphenyl 775 Butyl 3-Chlorophenyl776 Pentyl 5-Chloro-2-methoxyphenyl 777 3-Methylbutyl 2,5-Dichlorophenyl778 Butyl Phenyl 779 2-Methylpropyl 3-Methylphenyl 780 2-Methylpropyl3-Fluoro-4-methylphenyl 781 2-Methylpropyl 3-Chlorophenyl 7823-Methylbutyl 5-Chloro-2-methoxyphenyl 783 Butyl 5-Methyl-2-thienyl 7842-Methylpropyl Phenyl 785 Pentyl 3-Methylphenyl 786 3-Methylbutyl3-Fluoro-4-methylphenyl 787 Pentyl 3-Chlorophenyl 788 Butyl2,5-Dichlorophenyl 789 2-Methylpropyl 5-Methyl-2-thienyl 790 PentylPhenyl 791 3-Methylbutyl 3-Methylphenyl 792 Pentyl5-Fluoro-2-methylphenyl 793 3-Methylbutyl 3-Chlorophenyl 7942-Methylpropyl 4-Methylthiophenyl 795 2-Methylpropyl3-Fluoro-4-methoxyphenyl 796 3-Methylbutyl 3-Fluoro-4-methoxyphenyl 7972-Methylpropyl 2,4,6-Trifluorophenyl 798 Butyl 2,3,6-Trifluorophenyl 7992-Methylpropyl 2,3,6-Trifluorophenyl 885 Methyl 2,3,6-Trifluorophenyl886 Propyl 2,3,6-Trifluorophenyl 933 Propyl Phenyl 934 Propyl3-Fluorophenyl 935 Propyl 4-Fluorophenyl 936 Allyl 2-Fluorophenyl 937Propyl 2-Fluorophenyl 1037 Butyl 3-Chlorophenyl 1038 2-Methylpropyl3-Chlorophenyl 1039 Pentyl 3-Chlorophenyl 1040 3-Methylbutyl3-Chlorophenyl 1041 Butyl 3,4-Difluorophenyl 1042 2-Methylpropyl3,4-Difluorophenyl 1043 Pentyl 3,4-Difluorophenyl 1044 3-Methylbutyl3,4-Difluorophenyl 1045 Butyl 2,3-Difluorophenyl 1046 2-Methylpropyl2,3-Difluorophenyl 1047 Pentyl 2,3-Difluorophenyl 1048 3-Methylbutyl2,3-Difluorophenyl 1049 Butyl 2,5-Difluorophenyl 1050 2-Methylpropyl2,5-Difluorophenyl 1051 Pentyl 2,5-Difluorophenyl 1052 3-Methylbutyl2,5-Difluorophenyl 1053 Butyl 2,4-Difluorophenyl 1054 2-Methylpropyl2,4-Difluorophenyl 1055 Pentyl 2,4-Difluorophenyl 1056 3-Methylbutyl2,4-Difluorophenyl 1057 2-Methylpropyl 4-Propylphenyl 10582-Methylpropyl 4-Ethoxyphenyl 1059 Butyl 1,3-Benzodioxol-5-yl 10602-Methylpropyl 1,3-Benzodioxol-5-yl 1061 Pentyl 1,3-Benzodioxol-5-yl1062 3-Methylbutyl 1,3-Benzodioxol-5-yl 1063 Butyl 4-Methylothiophenyl1064 2-Methylpropyl 4-Methylothiophenyl 1065 Butyl3-Fluoro-4-methoxyphenyl 1066 2-Methylpropyl 3-Fluoro-4-methoxyphenyl1067 3-Methylbutyl 3-Fluoro-4-methoxyphenyl 1068 2-Methylpropyl4-Chloro-3-methylphenyl 1069 3-Methylbutyl 4-Chloro-3-methylphenyl 1070Butyl 3-Chloro-4-fluorophenyl 1071 2-Methylpropyl3-Chloro-4-fluorophenyl 1072 Pentyl 3-Chloro-4-fluorophenyl 10733-Methylbutyl 3-Chloro-4-fluorophenyl 1074 2-Methylpropyl3,4,5-Trifluorophenyl 1075 3-Methylbutyl 3,4,5-Trifluorophenyl 10762-Methylpropyl 4-Ethylthiophenyl 1077 3-Methylbutyl2,3,6-Trifluorophenyl 1078 Allyl 5-Chloro-2-methoxyphenyl 1079 Propyl5-Chloro-2-methoxyphenyl 1080 Propyl 3-Trifluoromethylphenyl 1081 Allyl2,5-Dichlorophenyl 1082 Propyl 2,5-Dichlorophenyl 1083 Methyl3-Bromophenyl 1084 Allyl 3-Bromophenyl 1085 Propyl3-Bromo-4-fluorophenyl 1086 Methyl 3-Iodophenyl 1087 Allyl 3-Iodophenyl1088 Propyl 3-Iodophenyl 1089 2-Methoxyethyl 2,5-Difluorophenyl 10902-Methoxyethyl 2,5-Dichlorophenyl 1091 2-Methoxyethyl 3-Bromophenyl 11452-Methylpropyl 3-Chloro-4-methoxyphenyl 1146 3-Methylbutyl3-Chloro-4-methoxyphenyl 1147 2-Methylpropyl 5-Chloro-2-methoxyphenyl1148 Pentyl 5-Chloro-2-methoxyphenyl 1149 3-Methylbutyl5-Chloro-2-methoxyphenyl 1150 Pentyl 3-Trifluoromethylphenyl 11513-Methylbutyl 3-Trifluoromethylphenyl 1152 Butyl 2-Trifluoromethylphenyl1153 3-Methylbutyl 2-Trifluoromethylphenyl 1154 Butyl 3,4-Dichlorophenyl1155 2-Methylpropyl 3,4-Dichlorophenyl 1156 3-Methylbutyl3,4-Dichlorophenyl 1157 2-Methylpropyl 2,5-Dichlorophenyl 1158 Pentyl2,5-Dichlorophenyl 1159 3-Methylbutyl 2,5-Dichlorophenyl 11602-Methylpropyl 2,4-Dichlorophenyl 1161 2-Methylpropyl 3-Bromophenyl 1162Pentyl 3-Bromophenyl 1163 3-Methylbutyl 3-Bromophenyl 11642-Methylpropyl 4-Bromophenyl 1165 2-Methylpropyl 2-Bromophenyl 1166Pentyl 2-Bromophenyl 1167 3-Methylbutyl 2-Bromophenyl 11942-Methylpropyl 3-Phenoxyphenyl 1195 2-Methylpropyl 4-Phenoxyphenyl 1196Butyl 3-Bromo-4-methylphenyl 1197 2-Methylpropyl 3-Bromo-4-methylphenyl1198 Butyl 3-Bromo-4-fluorophenyl 1199 2-Methylpropyl3-Bromo-4-fluorophenyl 1200 Pentyl 3-Bromo-4-fluorophenyl 12013-Methylbutyl 3-Bromo-4-fluorophenyl 1202 Butyl 3-Iodophenyl 1203 Pentyl3-Iodophenyl 1204 3-Methylbutyl 3-Iodophenyl 1205 2-Methylpropyl4-Iodophenyl 1206 Methyl 3-Iodophenyl 1239 Cyclopentyl 4-Methylphenyl1240 Cyclopentyl 3-Fluoro-4-methylphenyl 1241 Cyclopropyl5-Chloro-2-methoxyphenyl Methyl 1242 Cyclopropyl 3-TrifluoromethylphenylMethyl 1243 Cyclopropyl 2,5-Dichlorophenyl Methyl 1244 Cyclopropyl3-Bromophenyl Methyl 1245 Cyclopentyl 3-Methoxybenzyl 1246 Cyclopentyl2-(2-Chlorophenyl) ethenyl 1247 Cyclopropyl 3-Bromo-4-methylphenylMethyl 1248 Cyclopropyl 3-Bromo-4-fluorophenyl Methyl 1249 Cyclopropyl3-Iodophenyl Methyl 1253 Cyclopentyl 3-Chloro-4-methoxyphenyl 1254Cyclopropyl 5-Chloro-2-methoxyphenyl Methyl 1255 Cyclopentyl2,4-Dichlorophenyl 1268 Cyclopentyl 3-Fluorobenzyl 1269 Cyclopentyl2-(2- Trifluoromethylphenyl) ethenyl 1270 Cyclopentyl 2-(2-Bromophenyl)ethenyl 1271 Cyclopropyl 2,3,6-Trifluorophenyl Methyl 1274 Cyclopentyl3-Chloro-4-methylphenyl 1275 Cyclopropyl 2,4,5-Trifluorophenyl Methyl1425 Propyl 3-Fluoro-4-methylphenyl 1426 Propyl 3-Chlorophenyl 1427Allyl 3-Bromo-4-fluorophenyl 1428 Propyl 3-Bromo-4-fluorophenyl 1429Allyl 3-Iodophenyl 1430 Propyl 3-Iodophenyl 1431 Propyl3-Iodo-4-methylphenyl 1433 Propyl 3,4-Difluorophenyl 1434 Propyl2,3-Difluorophenyl 1435 Propyl 2,4-Difluorophenyl 1436 Propyl1,3-Benzodioxol-5-yl 1437 Propyl 3-Chloro-4-fluorophenyl 1438 Propyl5-Chloro-2-methoxyphenyl 1439 Methyl 2,5-Dichlorophenyl 1440 Allyl2,5-Dichlorophenyl 1441 Propyl 2,5-Dichlorophenyl 1442 Propyl2,4-Dichlorophenyl 1443 Methyl 3-Bromophenyl 1444 Allyl 3-Bromophenyl1445 Propyl 3-Bromophenyl 1446 Propyl 5-Methyl-2-thienyl 1447 Propyl2,6-Difluorophenyl 1977 3-Methylbutyl 4,5-Dimethyl-2-furyl 19783-Methylbutyl 3-Chloro-4-methylphenyl 1980 3-Methylbutyl2,4,5-Trifluorophenyl 1982 3-Methylbutyl 2,6-Difluorophenyl 19833-Methylbutyl 2-Bromo-5-methoxyphenyl 1984 3-Methylbutyl3,5-Difluorophenyl 2006 3-Methylbutyl 5-Bromo-2-thienyl 20083-Methylbutyl 3-Bromo-2-thienyl

EXAMPLE 13

For each compound, the definitions of R₂ and R₃ are specified in thefollowing table.

Compound No. R₂ R₃ 800 Propyl Phenyl 801 Methyl 3-Chlorophenyl 802 Allyl3-Chlorophenyl 803 Propyl 3-Chlorophenyl 804 Propyl5-Chloro-2-methoxyphenyl 805 Propyl 3-Trifluoromethylphenyl 806 Propyl2,5-Dichlorophenyl 807 Propyl 3-Bromophenyl 808 Propyl3-Bromo-4-fluorophenyl 809 Methyl 3-Iodophenyl 810 Allyl 3-Iodophenyl811 Propyl 3-Iodophenyl 888 Allyl 5-Chloro-2-methoxyphenyl 931 Propyl3-Fluorophenyl 932 Propyl 2-Fluorophenyl 1092 Propyl 3-Fluorophenyl 1093Propyl 2-Fluorophenyl 1094 Allyl 2,5-Difluorophenyl 1095 Propyl2,5-Difluorophenyl 1096 Propyl 1,3-Benzodioxol-5-yl 1097 Methyl5-Chloro-2-methoxyphenyl 1098 Allyl 5-Chloro-2-methoxyphenyl 1099 Methyl2,5-Dichlorophenyl 1168 Methyl 5-Chloro-2-methoxyphenyl 1169 Allyl5-Chloro-2-methoxyphenyl 1170 Propyl 5-Chloro-2-methoxyphenyl 1171Propyl 3,4-Dichlorophenyl 1172 Allyl 2,5-Dichlorophenyl 1173 Propyl2,5-Dichlorophenyl 1174 Propyl 2,4-Dichlorophenyl 1175 Methyl3-Bromophenyl 1176 Allyl 3-Bromophenyl 1177 Propyl 3-Bromophenyl 1178Cyclopropyl 5-Chloro-2-methoxyphenyl methyl 1179 Cyclopropyl2,5-Dichlorophenyl methyl 1180 Propyl 3-Bromophenyl 1181 Cyclopropyl3-Bromophenyl methyl 1182 Pentyl 3-Bromo-4-fluorophenyl 11833-Methylbutyl 3-Bromo-4-fluorophenyl 1184 Pentyl 3-Iodophenyl 1185Cyclopropyl 3-Bromo-4-fluorophenyl Methyl 1186 Cyclopropyl 3-IodophenylMethyl 1756 Butyl 2-Thienyl 1757 2-Methylpropyl 2-Thienyl 1758 Pentyl2-Thienyl 1759 3-Methylbutyl 2-Thienyl 1760 Butyl 3-Thienyl 17612-Methylpropyl 3-Thienyl 1762 Pentyl 3-Thienyl 1763 3-Methylbutyl3-Thienyl 1764 3-Methylbutyl Benzyl 1765 Butyl 5-Methyl-2-thienyl 17662-Methylpropyl 5-Methyl-2-thienyl 1767 Pentyl 5-Methyl-2-thienyl 17683-Methylbutyl 5-Methyl-2-thienyl 1769 3-Methylbutyl 3-Fluorobenzyl 17703-Methylbutyl 4-Fluorobenzyl 1771 3-Methylbutyl 3-Methoxybenzyl 17873-Methylbutyl 2,3,6-Trifluorophenyl 1788 2-Methylpropyl2,3,6-Trifluorophenyl 1789 3-Methylbutyl 2,3,6-Trifluorophenyl 17903-Methylbutyl 2-Chloro-6-fluorophenyl 1791 Butyl Phenyl 17922-Methylpropyl Phenyl 1793 Pentyl Phenyl 1794 3-Methylbutyl Phenyl 1795Butyl 3-Methylphenyl 1796 2-Methylpropyl 3-Methylphenyl 1797 Pentyl3-Methylphenyl 1798 3-Methylbutyl 3-Methylphenyl 1799 Butyl4-Methylphenyl 1800 2-Methylpropyl 4-Methylphenyl 1801 Butyl3-Fluorophenyl 1802 2-Methylpropyl 3-Fluorophenyl 1803 Pentyl3-Fluorophenyl 1804 3-Methylbutyl 3-Fluorophenyl 1805 Butyl4-Fluorophenyl 1806 3-Methylbutyl 4-Fluorophenyl 1807 Butyl2-Fluorophenyl 1808 2-Methylpropyl 2-Fluorophenyl 1809 Pentyl2-Fluorophenyl 1810 3-Methylbutyl 2-Fluorophenyl 1811 2-Methylpropyl4-Ethylphenyl 1812 2-Methylpropyl 3,4-Dimethylphenyl 1813 3-Methylbutyl3-Methoxyphenyl 1814 2-Methylpropyl 3-Fluoro-4-methylphenyl 18153-Methylbutyl 3-Fluoro-4-methylphenyl 1816 2-Methylpropyl5-Fluoro-2-methylphenyl 1817 Pentyl 5-Fluoro-2-methylphenyl 18183-Methylbutyl 5-Fluoro-2-methylphenyl 1857 Butyl 2,5-Dichlorophenyl 18582-Methylpropyl 2,5-Dichlorophenyl 1859 Pentyl 2,5-Dichlorophenyl 18603-Methylbutyl 2,5-Dichlorophenyl 1861 2-Methylpropyl 4-Pentylphenyl 1862Butyl 3-Bromophenyl 1863 2-Methylpropyl 3-Bromophenyl 1864 Pentyl3-Bromophenyl 1865 3-Methylbutyl 3-Bromophenyl 1866 2-Methylpropyl4-Bromophenyl 1922 Butyl 3,4-Dimethylphenyl 1923 2-Methylpropyl3-Iodo-4-methylphenyl 1924 3-Methylbutyl 3-Iodo-4-methylphenyl 1986Butyl 4,5-Dimethyl-2-furyl 1987 2-Methylpropyl 4,5-Dimethyl-2-furyl 19883-Methylbutyl 4,5-Dimethyl-2-furyl 1989 3-Methylbutyl4-Methoxy-3-thienyl 1990 Butyl 3-Chloro-2-thienyl 1991 2-Methylpropyl3-Chloro-2-thienyl 1992 Pentyl 3-Chloro-2-thienyl 1993 3-Methylbutyl3-Chloro-2-thienyl 1994 2-Methylpropyl 3-Chloro-4-methylphenyl 19953-Methylbutyl 3-Chloro-4-methylphenyl 1996 3-Methylbutyl2,4,5-Trifluorophenyl 1997 Pentyl 2,6-Difluorophenyl 1998 3-Methylbutyl2,6-Difluorophenyl 1999 Pentyl 2-Bromo-5-methoxyphenyl 20003-Methylbutyl 2-Bromo-5-methoxyphenyl 2001 3-Methylbutyl3,5-Difluorophenyl 2002 2-Methylpropyl 5-Bromo-2-thienyl 20033-Methylbutyl 5-Bromo-2-thienyl 2009 Butyl 5-Ethyl-2-thienyl 20102-Methylpropyl 5-Ethyl-2-thienyl 2011 3-Methylbutyl 5-Ethyl-2-thienyl2012 2-Methylpropyl 5-Propyl-2-thienyl 2013 2-Methylpropyl5-Butyl-2-thienyl 2014 2-Methylpropyl 5-Pentyl-2-thienyl 20152-Methylpropyl 5-Hexyl-2-thienyl

EXAMPLE 14

For each compound, the definitions of R₂ and R₃ are specified in thefollowing table.

Compound No. R₂ R₃ 889 Methyl 2,5-Difluorophenyl 890 Methyl2,5-Dichlorophenyl 891 Propyl 3-Bromophenyl 892 Methyl 3-Iodophenyl 893Allyl 3-Iodophenyl 894 Propyl 3-Iodophenyl 1126 Propyl2,5-Dichlorophenyl 1127 Methyl 3-Bromophenyl 1128 Allyl 3-Bromophenyl1432 Propyl 3-Bromo-4-fluorophenyl 1517 2-Methylpropyl 3-Fluorophenyl1518 2-Methylpropyl 3,4-Dimethylphenyl 1519 2-Methylpropyl3-Methoxyphenyl 1520 2-Methylpropyl 3-Fluoro-4-methylphenyl 1521Cyclopentyl 3-Fluoro-4-methylphenyl 1522 2-Methylpropyl5-Fluoro-2-methylphenyl 1523 2-Methylpropyl 2-Fluoro-3-methylphenyl 15242-Methylpropyl 3-Chlorophenyl 1525 2-Methylpropyl 4-Chlorophenyl 15672-Methylpropyl 1,3-Benzodioxol-5-yl 1568 Cyclopentyl 4-Methoxyphenyl1569 Cyclopentyl 4-Butylphenyl 1570 3-Methylbutyl3-Chloro-4-methoxyphenyl 1571 Cyclopentyl 3-Chloro-4-methoxyphenyl 15722-Methylpropyl 3,4-Dichlorophenyl 1573 3-Methylbutyl 2,5-Dichlorophenyl1574 Cyclopentyl 2,4-Dichlorophenyl 1575 Cyclopentyl 4-Pentylphenyl 15763-Methylbutyl 3-Bromophenyl 1619 2-Methylpropyl 4-Hexylphenyl 1620Cyclopentyl 4-Hexylphenyl 1621 2-Methylpropyl 3-Bromo-4-methylphenyl1622 2-Methylpropyl 3-Bromo-4-fluorophenyl 1623 3-Methylbutyl3-Bromo-4-fluorophenyl 1624 2-Methylpropyl 3-Iodophenyl 16253-Methylbutyl 3-Iodophenyl 1653 2-Methylpropyl 3-Iodo-4-methylphenyl1654 3-Methylbutyl 2-Thienyl 1655 3-Methylbutyl Benzyl 16562-Methylpropyl 5-Methyl-2-thienyl 1657 3-Methylbutyl 5-Methyl-2-thienyl1658 3-Methylbutyl 3-Fluorobenzyl 1659 Cyclopentyl 3-Fluorobenzyl 1678Cyclopentyl 2-Chlorobenzyl 1682 2-Methylpropyl 2-(2-Chlorophenyl)ethenyl 1683 Cyclopentyl 2-(2-Chlorophenyl) ethenyl 1701 2-Methylpropyl2,3,6-Trifluorophenyl 1702 2-Methylpropyl 4,5-Dimethyl-2-furyl

EXAMPLE 15

For each compound, the definitions of R₂ and R₃ are specified in thefollowing table.

Compound No. R₂ R₃ 895 Propyl 5-Bromo-2-thienyl 993 Propyl1,3-Benzodioxol-5-yl

EXAMPLE 16

For each compound, the definitions of R₂ and R₃ are specified in thefollowing table.

Compound No. R₂ R₃ 896 Propyl 3-Bromo-4-fluorophenyl 897 Allyl3-Iodophenyl 898 Propyl 3-Iodophenyl 899 Propyl 3-Iodo-4-methylphenyl900 Methyl 2-Thienyl 901 Methyl 5-Methyl-2-thienyl 923 Propyl3-Methylphenyl 1117 Propyl 5-Chloro-2-methoxyphenyl 1118 Propyl2,5-Dichlorophenyl 1119 Propyl 3-Bromophenyl 1979 3-Methylbutyl3-Chloro-4-methylphenyl 1981 3-Methylbutyl 2,4,5-Trifluorophenyl 19853-Methylbutyl 3,5-Difluorophenyl 2007 3-Methylbutyl 5-Bromo-2-thienyl2386 2-(2- 2,5-Dichlorophenyl Fluorophenyl) ethyl 2387 2-(2-3-Bromophenyl Fluorophenyl) ethyl 2388 2-(2- 3-Iodophenyl Fluorophenyl)ethyl

EXAMPLE 17

For each compound, the definitions of R₂ and R₃ are specified in thefollowing table.

Compound No. R₂ R₃ 902 Allyl 3-Bromo-4-methylphenyl 903 Propyl3-Bromo-4-methylphenyl 904 Allyl 3-Bromo-4-fluorophenyl 905 Propyl3-Bromo-4-fluorophenyl 906 Methyl 3-Iodophenyl 907 Allyl 3-Iodophenyl908 Propyl 3-Iodophenyl 909 Propyl 3-Iodo-4-methylphenyl 910 Methyl2-Thienyl 911 Methyl 3-Thienyl 912 Methyl 3-Methyl-2-thienyl 913 Propyl5-Methyl-2-thienyl 914 Propyl Phenyl 915 Methyl 3-Methylphenyl 916Propyl 3-Fluorophenyl 917 Propyl 2-Fluorophenyl 918 Methyl5-Fluoro-2-methylphenyl 919 Allyl 5-Fluoro-2-methylphenyl 920 Methyl3-Chlorophenyl 921 Propyl 3-Chlorophenyl 976 Propyl 2-Chlorophenyl 977Allyl 3,4-Difluorophenyl 978 Propyl 3,4-Difluorophenyl 979 Methyl2,3-Difluorophenyl 980 Allyl 2,3-Difluorophenyl 981 Propyl2,3-Difluorophenyl 982 Methyl 2,5-Difluorophenyl 983 Allyl2,5-Difluorophenyl 984 Propyl 2,5-Difluorophenyl 985 Propyl2,4-Difluorophenyl 986 Propyl 1,3-Benzodioxol-5-yl 987 Allyl3-Chloro-4-fluorophenyl 988 Propyl 3-Chloro-4-fluorophenyl 1120 Allyl5-Chloro-2-methoxyphenyl 1121 Propyl 5-Chloro-2-methoxyphenyl 1122 Allyl2,5-Dichlorophenyl 1123 Propyl 2,5-Dichlorophenyl 1124 Allyl3-Bromophenyl 1125 Propyl 3-Bromophenyl 1516 Methyl 5-Ethoxy-2-thienyl1706 2-Methylpropyl 2,4,6-Trifluorophenyl 1707 2-Methylpropyl2,3,6-Trifluorophenyl 1708 3-Methylbutyl 2,3,6-Trifluorophenyl 17092-Methylpropyl 4,5-Dimethyl-2-furyl 1710 3-Methylbutyl4,5-Dimethyl-2-furyl 1711 2-Methylpropyl 3-Chloro-2-thienyl 17123-Methylbutyl 3-Chloro-2-thienyl 1713 2-Methylpropyl5-Methylthio-2-thienyl 1719 2-Methylpropyl 3-Chlorophenyl 17203-Methylbutyl 2,4,5-Trifluorophenyl 1725 2-Methylpropyl2,6-Difluorophenyl 1727 3-Methylbutyl Phenyl 1728 2-Methylpropyl3-Methylphenyl 1729 3-Methylbutyl 3-Methylphenyl 1730 2-Methylpropyl4-Methylphenyl 1731 3-Methylbutyl 4-Methylphenyl 1732 2-Methylpropyl2-Methylphenyl 1733 3-Methylbutyl 2-Methylphenyl 1734 2-Methylpropyl3-Fluorophenyl 1735 3-Methylbutyl 3-Fluorophenyl 1736 2-Methylpropyl3-Fluorophenyl 1737 3-Methylbutyl 4-Fluorophenyl 1738 2-Methylpropyl2-Fluorophenyl 1739 3-Methylbutyl 2-Fluorophenyl 1740 2-Methylpropyl4-Ethylphenyl) 1741 2-Methylpropyl 3,4-Dimethylphenyl 17422-Methylpropyl 3-Fluoro-4-methylphenyl 1743 Cyclopentyl3-Fluoro-4-methylphenyl 1744 2-Methylpropyl 4-Chlorophenyl 1745Cyclopentyl 4-Methoxyphenyl 1746 3-Methylbutyl 3-Chloro-4-fluorophenyl1747 3-Methylbutyl 2-Thienyl

EXAMPLE 18

For each compound, the definitions of R₂ and R₃ are specified in thefollowing table.

Compound No. R₂ R₃ 812 Methyl 2,5-Difluorophenyl 813 Propyl2,5-Dichlorophenyl 814 Propyl 3-Iodophenyl

EXAMPLE 19

For each compound, the definitions of R₂ and R₃ are specified in thefollowing table.

Compound No. R₂ R₃ 818 Propyl 3-Fluorophenyl 819 Propyl 2-Fluorophenyl820 Propyl 3,4-Difluorophenyl 821 Methyl 2,5-Difluorophenyl 822 Allyl2,5-Difluorophenyl 823 Propyl 2,5-Difluorophenyl 824 Propyl1,3-Benzodioxol-5-yl 825 Propyl 3-Chloro-4-fluorophenyl 826 Methyl5-Chloro-2-methoxyphenyl 827 Ethyl 5-Chloro-2-methoxyphenyl 828 Allyl5-Chloro-2-methoxyphenyl 829 Propyl 5-Chloro-2-methoxyphenyl 830 Methyl2,5-Dichlorophenyl 831 Allyl 2,5-Dichlorophenyl 832 Propyl2,5-Dichlorophenyl 833 Propyl Phenyl 834 Propyl 3-Fluoro-4-methylphenyl835 Propyl 5-Fluoro-2-methylphenyl 836 Methyl 3-Chlorophenyl 837 Allyl3-Chlorophenyl 838 Propyl 3-Chlorophenyl 842 Methyl5-Chloro-2-methoxyphenyl 843 Ethyl 5-Chloro-2-methoxyphenyl 844 Allyl5-Chloro-2-methoxyphenyl 845 Propyl 5-Chloro-2-methoxyphenyl 846 Methyl3-Trifluorophenyl 847 Propyl 3-Trifluorophenyl 848 Methyl2,5-Dichlorophenyl 849 Allyl 2,5-Dichlorophenyl 850 Propyl2,5-Dichlorophenyl 851 Methyl 3-Bromophenyl 852 Allyl 3-Bromophenyl 853Propyl 3-Bromophenyl 854 Propyl 3-Bromo-4-fluorophenyl 855 Methyl3-Iodophenyl 856 Allyl 3-Iodophenyl 857 Propyl 3-Iodophenyl 859 Allyl2-Fluorophenyl 860 Propyl 2-Fluorophenyl 861 Propyl 2-Chlorophenyl 862Propyl 3,4-Difluorophenyl 863 Propyl 2,3-Difluorophenyl 864 Methyl2,5-Difluorophenyl 865 Propyl 4-Methylthio phenyl 866 Propyl3-Fluoro-4-methoxphenyl 867 Propyl 4-Chloro-3-methylphenyl 868 Methyl3-Chloro-4-fluorophenyl 869 Allyl 3-Chloro-4-fluorophenyl 870 Propyl3-Chloro-4-fluorophenyl 871 Propyl 3,4,5-Trifluorophenyl 872 Propyl4-Butylphenyl 873 Propyl 4-Methylthio phenyl 1772 Butyl 2-Thienyl 17732-Methylpropyl 2-Thienyl 1774 Pentyl 2-Thienyl 1775 3-Methylbutyl2-Thienyl 1776 Butyl 3-Thienyl 1777 2-Methylpropyl 3-Thienyl 1778 Pentyl3-Thienyl 1779 3-Methylbutyl 3-Thienyl 1780 3-Methylbutyl Benzyl 1781Butyl 5-Methyl-2-thienyl 1782 2-Methylpropyl 5-Methyl-2-thienyl 1783Pentyl 5-Methyl-2-thienyl 1784 3-Methylbutyl 5-Methyl-2-thienyl 17853-Methylbutyl 3-Fluorobenzyl 1786 3-Methylbutyl 3-Methoxybenzyl 1819Butyl Phenyl 1820 2-Methylpropyl Phenyl 1821 Pentyl Phenyl 18223-Methylbutyl Phenyl 1823 Butyl 3-Methylphenyl 1824 2-Methylpropyl3-Methylphenyl 1825 Pentyl 3-Methylphenyl 1826 3-Methylbutyl3-Methylphenyl 1827 Butyl 4-Methylphenyl 1828 2-Methylpropyl4-Methylphenyl 1829 3-Methylbutyl 4-Methylphenyl 1830 Butyl3-Fluorophenyl 1831 2-Methylpropyl 3-Fluorophenyl 1832 Pentyl3-Fluorophenyl 1833 3-Methylbutyl 3-Fluorophenyl 1834 Butyl4-Fluorophenyl 1835 2-Methylpropyl 4-Fluorophenyl 1836 Pentyl4-Fluorophenyl 1837 3-Methylbutyl 4-Fluorophenyl 1838 Butyl2-Fluorophenyl 1839 2-Methylpropyl 2-Fluorophenyl 1840 Pentyl2-Fluorophenyl 1841 3-Methylbutyl 2-Fluorophenyl 1842 2-Methylpropyl4-Ethylphenyl 1843 2-Methylpropyl 3,4-Dimethylphenyl 1844 3-Methylbutyl2,5-Dimethylphenyl 1845 2-Methylpropyl 2,4-Dimethylphenyl 18462-Methylpropyl 3-Methoxyphenyl 1847 3-Methylbutyl 3-Methoxyphenyl 18483-Methylbutyl 2-Methoxyphenyl 1849 2-Methylpropyl3-Fluoro-4-methylphenyl 1850 3-Methylbutyl 3-Fluoro-4-methylphenyl 1851Butyl 5-Fluoro-2-methylphenyl 1852 2-Methylpropyl5-Fluoro-2-methylphenyl 1853 Pentyl 5-Fluoro-2-methylphenyl 18543-Methylbutyl 5-Fluoro-2-methylphenyl 1855 2-Methylpropyl 4-Chlorophenyl1856 3-Methylbutyl 4-Chlorophenyl 1867 2-Methylpropyl 2,5-Dichlorophenyl1868 Pentyl 2,5-Dichlorophenyl 1869 3-Methylbutyl 2,5-Dichlorophenyl1870 2-Methylpropyl 4-Pentylphenyl 1871 2-Methylpropyl 3-Bromophenyl1872 Pentyl 3-Bromophenyl 1873 3-Methylbutyl 3-Bromophenyl 19252-Methylpropyl 3-Iodo-4-methylphenyl 1926 3-Methylbutyl3-Iodo-4-methylphenyl 1928 Butyl 2-Chlorophenyl 1929 2-Methylpropyl2-Chlorophenyl 1930 Pentyl 2-Chlorophenyl 1931 Butyl 3,4-Difluorophenyl1932 2-Methylpropyl 3,4-Difluorophenyl 1933 Pentyl 3,4-Difluorophenyl1934 3-Methylbutyl 3,4-Difluorophenyl 1935 Butyl 2,3-Difluorophenyl 19362-Methylpropyl 2,3-Difluorophenyl 1937 Pentyl 2,3-Difluorophenyl 19383-Methylbutyl 2,3-Difluorophenyl 1939 Butyl 2,5-Difluorophenyl 19402-Methylpropyl 2,5-Difluorophenyl 1941 Pentyl 2,5-Difluorophenyl 19423-Methylbutyl 2,5-Difluorophenyl 1943 Butyl 2,4-Difluorophenyl 19442-Methylpropyl 2,4-Difluorophenyl 1945 Pentyl 2,4-Difluorophenyl 19463-Methylbutyl 2,4-Difluorophenyl 1947 2-Methylpropyl 4-Propylphenyl 19482-Methylpropyl 4-i-Propylphenyl 1949 Butyl 1,3-Benzodioxol-5-yl 19502-Methylpropyl 1,3-Benzodioxol-5-yl 1951 Pentyl 1,3-Benzodioxol-5-yl1952 3-Methylbutyl 1,3-Benzodioxol-5-yl 1953 Butyl3-Bromo-4-methylphenyl 1954 2-Methylpropyl 3-Bromo-4-methylphenyl 1955Pentyl 3-Bromo-4-Methylphenyl 1956 3-Methylbutyl 3-Bromo-4-methylphenyl1957 2-Methylpropyl 4-Heptylphenyl 1958 Butyl 3-Iodophenyl 19592-Methylpropyl 3-Iodophenyl 1960 Pentyl 3-Iodophenyl 1961 3-Methylbutyl3-Iodophenyl 1962 2-Methylpropyl 4-Iodophenyl 2016 Butyl5-Ethyl-2-thienyl 2017 2-Methylpropyl 5-Ethyl-2-thienyl 20183-Methylbutyl 5-Ethyl-2-thienyl 2019 2-Methylpropyl 5-Propyl-2-thienyl

EXAMPLE 20

For each compound, the definitions of R₂ and R₃ are specified in thefollowing table.

Compound No. R₂ R₃ 874 Methyl 3-Fluorophenyl 875 Allyl 3-Fluorophenyl876 Propyl 3-Fluorophenyl 877 Propyl 4-Fluorophenyl 878 Methyl3-Chloro-4-methylphenyl 879 Allyl 3-Chloro-4-methylphenyl 880 Propyl3-Chloro-4-methylphenyl 881 Allyl 5-Bromo-2-thienyl 882 Propyl5-Bromo-2-thienyl 883 Propyl 3-Fluoro-4-methylphenyl 884 Propyl5-Fluoro-2-methylphenyl 922 Propyl 3-Methoxyphenyl 1450 Propyl3-Bromo-4-methylphenyl 1451 Allyl 3-Bromo-4-fluorophenyl 1452 Propyl3-Bromo-4-fluorophenyl 1453 Allyl 3-Iodophenyl 1454 Propyl 3-Iodophenyl1455 Allyl 5-Chloro-2-methoxyphenyl 1456 Propyl 5-Chloro-2-methoxyphenyl1457 Propyl 3,4-Dichlorophenyl 1458 Ethyl 2,5-Dichlorophenyl 1459 Allyl2,5-Dichlorophenyl 1460 Propyl 2,5-Dichlorophenyl 1461 Propyl2,4-Dichlorophenyl 1462 Ethyl 3-Bromophenyl 1463 Allyl 3-Bromophenyl1464 Propyl 3-Bromophenyl 1465 Propyl 5-Methyl-2-thienyl 1466 Propyl4-Chloro-3-methylphenyl 1467 Propyl 3-Chloro-4-fluorophenyl 15262-Methylpropyl Phenyl 1527 3-Methylbutyl Phenyl 1528 2-Methylpropyl3-Methylphenyl 1529 3-Methylbutyl 3-Methylphenyl 1530 2-Methylpropyl4-Methylphenyl 1531 Cyclopentyl 4-Methylphenyl 1532 2-Methylpropyl2-Methylphenyl 1533 3-Methylbutyl 2-Methylphenyl 1534 2-Methylpropyl3-Fluorophenyl 1535 3-Methylbutyl 3-Fluorophenyl 1536 2-Methylpropyl4-Fluorophenyl 1537 3-Methylbutyl 4-Fluorophenyl 1538 2-Methylpropyl2-Fluorophenyl 1539 Cyclopentyl 2-Fluorophenyl 1540 2-Methylpropyl4-Ethylphenyl 1541 2-Methylpropyl 3,4-Dimethylphenyl 1542 2-Methylpropyl2,3-Dimethylphenyl 1543 2-Methylpropyl 2,5-Dimethylphenyl 15443-Methylbutyl 2,5-Dimethylphenyl 1545 2-Methylpropyl 2,4-Dimethylphenyl1546 3-Methylbutyl 2,4-Dimethylphenyl 1547 Cyclopentyl2,4-Dimethylphenyl 1548 2-Methylpropyl 3-Methoxyphenyl 15493-Methylbutyl 3-Methoxyphenyl 1550 2-Methylpropyl 4-Methoxyphenyl 15513-Methylbutyl 4-Methoxyphenyl 1552 Cyclopentyl 4-Methoxyphenyl 15532-Methylpropyl 2-Methoxyphenyl 1554 3-Methylbutyl 2-Methoxyphenyl 15552-Methylpropyl 3-Fluoro-4-methylphenyl 1556 Cyclopentyl3-Fluoro-4-methylphenyl 1557 2-Methylpropyl 3-Fluoro-2-methylphenyl 15583-Methylbutyl 3-Fluoro-2-methylphenyl 1559 2-Methylpropyl5-Fluoro-2-methylphenyl 1560 3-Methylbutyl 5-Fluoro-2-methylphenyl 15612-Methylpropyl 2-Fluoro-3-methylphenyl 1562 2-Methylpropyl3-Chlorophenyl 1563 3-Methylbutyl 3-Chlorophenyl 1564 Cyclopentyl3-Chlorophenyl 1565 2-Methylpropyl 4-Chlorophenyl 1566 Cyclopentyl4-Chlorophenyl 1577 3-Methylbutyl 2-Chlorophenyl 1578 Cyclopentyl2-Chlorophenyl 1579 2-Methylpropyl 3,4-Difluorophenyl 1580 3-Methylbutyl3,4-Difluorophenyl 1581 2-Methylpropyl 2,3-Difluorophenyl 15823-Methylbutyl 2,3-Difluorophenyl 1583 Cyclopentyl 2,3-Difluorophenyl1584 2-Methylpropyl 2,5-Difluorophenyl 1585 3-Methylbutyl2,5-Difluorophenyl 1586 2-Methylpropyl 2,4-Difluorophenyl 15873-Methylbutyl 2,4-Difluorophenyl 1588 Cyclopentyl 2,4-Difluorophenyl1589 2-Methylpropyl 1,3-Benzodioxol-5-yl 1590 3-Methylbutyl1,3-Benzodioxol-5-yl 1591 Cyclopentyl 1,3-Benzodioxol-5-yl 15922-Methylpropyl 4-Methylthiophenyl 1593 Cyclopentyl 4-Methylthiophenyl1594 Cyclopentyl 3-Fluoro-4-methoxy 1595 Cyclopentyl 4-Butylphenyl 1596Cyclopentyl 4-Ethylthiophenyl 1597 2-Methylpropyl3-Chloro-4-methoxyphenyl 1598 3-Methylbutyl 3-Chloro-4-methoxyphenyl1599 Cyclopentyl 3-Chloro-4-methoxyphenyl 1600 2-Methylpropyl2-Trifluoromethylphenyl 1601 3-Methylbutyl 2-Trifluoromethylphenyl 16022-Methylpropyl 3,4-Dichlorophenyl 1603 3-Methylbutyl 3,4-Dichlorophenyl1604 2-Methylpropyl 2,3-Dichlorophenyl 1605 2-Methylpropyl2,5-Dichlorophenyl 1606 3-Methylbutyl 2,5-Dichlorophenyl 16072-Methylpropyl 2,4-Dichlorophenyl 1608 Cyclopentyl 2,4-Dichlorophenyl1609 2-Methylpropyl 3-Bromophenyl 1610 3-Methylbutyl 3-Bromophenyl 1611Cyclopentyl 3-Bromophenyl 1612 2-Methylpropyl 4-Bromophenyl 1613Cyclopentyl 4-Bromophenyl 1614 2-Methylpropyl 2-Bromophenyl 16153-Methylbutyl 2-Bromophenyl 1626 2-Methylpropyl 3-Bromo-4-methylphenyl1627 3-Methylbutyl 3-Bromo-4-methylphenyl 1628 Cyclopentyl3-Bromo-4-methylphenyl 1629 2-Methylpropyl 3-Bromo-4-fluorophenyl 16303-Methylbutyl 3-Bromo-4-fluorophenyl 1631 2-Methylpropyl 3-Iodophenyl1632 3-Methylbutyl 3-Iodophenyl 1633 2-Methylpropyl 4-Iodophenyl 16602-Methylpropyl 3-Iodo-4-methylphenyl 1661 2-Methylpropyl 4-Iodobenzyl1662 2-Methylpropyl 2-Thienyl 1663 3-Methylbutyl 2-Thienyl 16642-Methylpropyl Benzyl 1665 3-Methylbutyl Benzyl 1666 Cyclopentyl Benzyl1667 2-Methylpropyl 5-Methyl-2-thienyl 1668 3-Methylbutyl5-Methyl-2-thienyl 1669 Cyclopentyl 5-Methyl-2-thienyl 1670 Cyclopentyl3-Methylbenzyl 1671 2-Methylpropyl 3-Fluorobenzyl 1672 3-Methylbutyl3-Fluorobenzyl 1673 Cyclopentyl 3-Fluorobenzyl 1679 3-Methylbutyl2-Methoxybenzyl 1680 Cyclopentyl 1-(4-Fluorophenyl) ethyl 1681Cyclopentyl 2-Chlorobenzyl 1684 Cyclopentyl 2-(2-Chlorophenyl) ethenyl1703 2-Methylpropyl 2,4,6-Trifluorophenyl 1704 2-Methylpropyl2,3,6-Trifluorophenyl 1705 2-Methylpropyl 2-Chloro-6-fluorophenyl 17142-Methylpropyl 3-Chloro-4-methylphenyl

EXAMPLE 21

For each compound, the definitions of R₂ and R₃ are specified in thefollowing table.

Compound No. R₂ R₃ 923 Propyl Phenyl 924 Propyl 3-Methylphenyl 925Propyl 4-Methylphenyl 926 Propyl 3-Fluorophenyl 927 Methyl2-Fluorophenyl 928 Allyl 2-Fluorophenyl 929 Propyl 2-Fluorophenyl 1000Methyl 2,3-Difluorophenyl 1001 Methyl 2,5-Difluorophenyl 1129 Ethyl5-Chloro-2-methoxyphenyl 2307 3-Methylbutyl 2,3,6-Trifluorophenyl

EXAMPLE 22

For each compound, the definitions of R₂ and R₃ are specified in thefollowing table.

Compound No. R₂ R₃ 955 Methyl Phenyl 956 Propyl Phenyl 957 Methyl3-Methylphenyl 958 Propyl 3-Methylphenyl 959 Methyl 3-Fluorophenyl 960Propyl 3-Fluorophenyl 961 Methyl 2-Fluorophenyl 962 Allyl 2-Fluorophenyl963 Propyl 2-Fluorophenyl 964 Methyl 5-Fluoro-2-methylphenyl 965 Methyl3-Chlorophenyl 966 Propyl 3-Chlorophenyl 989 Propyl3-Chloro-4-fluorophenyl 994 Methyl 2-Thienyl 995 Propyl 2-Thienyl 996Methyl 3-Thienyl 997 Methyl 3-Methyl-2-thienyl 998 Methyl5-Methyl-2-thienyl 999 Propyl 5-Methyl-2-thienyl 1100 Propyl5-Chloro-2-methoxyphenyl 1101 Methyl 3-Bromophenyl 1102 Propyl3-Bromophenyl

EXAMPLE 23

For each compound, the definitions of R₂ and R₃ are specified in thefollowing table.

Compound No. R₂ R₃ 967 Propyl Phenyl 968 Propyl 3-Methylphenyl 969Propyl 4-Methylphenyl 970 Propyl 3-Fluorophenyl 971 Propyl2-Fluorophenyl 972 Propyl 5-Fluoro-2-methylphenyl 973 Ethyl3-Chlorophenyl 974 Allyl 3-Chlorophenyl 975 Propyl 3-Chlorophenyl 990Propyl 1,3-Benzodioxol-5-yl 991 Allyl 3-Chloro-4-fluorophenyl 992 Propyl3-Chloro-4-fluorophenyl 1103 Propyl 5-Chloro-2-methoxyphenyl 1104 Propyl3-Trifluoromethylphenyl 1105 Propyl 3,4-Dichlorophenyl 1106 Allyl2,5-Dichlorophenyl 1107 Allyl 3-Bromophenyl 1108 Propyl 3-Bromophenyl1187 Propyl 3-Bromo-4-methylphenyl 1188 Methyl 3-Bromo-4-fluorophenyl1189 Allyl 3-Bromo-4-fluorophenyl 1190 Propyl 3-Bromo-4-fluorophenyl1191 Methyl 3-Iodophenyl 1192 Allyl 3-Iodophenyl 1193 Propyl3-Iodophenyl 1207 Propyl 3-Bromo-4-fluorophenyl 1208 Methyl3-Bromo-4-fluorophenyl 1209 Allyl 3-Bromo-4-fluorophenyl 1210 Propyl3-Bromo-4-fluorophenyl 1211 Methyl 3-Iodophenyl 1212 Ethyl 3-Iodophenyl1213 Allyl 3-Iodophenyl 1214 Propyl 3-Iodophenyl 1215 Propyl3-Iodo-4-methylphenyl 1216 Methyl 2-Thienyl 1217 Propyl 2-Thienyl 1218Allyl 5-Methyl-2-thienyl 1219 Propyl 5-Methyl-2-thienyl

EXAMPLE 24

For each compound, the definitions of R₂ and R₃ are specified in thefollowing table.

Compound No. R₂ R₃ 1220 2-Methylpropyl Phenyl 1221 2-Methylpropyl3-Methylphenyl 1222 2-Methylpropyl 4-Methylphenyl 1223 2-Methylpropyl2-Fluorophenyl 1224 2-Methylpropyl 4-Ethylphenyl 1225 2-Methylpropyl3,4-Dimethylphenyl 1227 2-Methylpropyl 2,5-Difluorophenyl 12282-Methylpropyl 2,4-Difluorophenyl 1229 2-Methylpropyl1,3-Benzodioxol-5-yl 1230 2-Methylpropyl 4-Bromophenyl 12512-Methylpropyl 3-Bromo-4-methylphenyl 1272 2-Methylpropyl3-Chloro-4-methylphenyl 1273 2-Methylpropyl 2,4,5-Trifluorophenyl

EXAMPLE 25

For each compound, the definitions of R₂ and R₃ are specified in thefollowing table.

Compound No. R₂ R₃ 1226 Propyl 2-Fluorophenyl 1231 Allyl5-Chloro-2-methoxyphenyl 1232 Propyl 5-Chloro-2-methoxyphenyl 1233Methyl 2,5-Dichlorophenyl 1234 Allyl 2,5-Dichlorophenyl 1235 Propyl2,5-Dichlorophenyl 1236 Methyl 3-Bromophenyl 1237 Allyl 3-Bromophenyl1238 Propyl 3-Bromophenyl 1252 Propyl 3-Iodophenyl 1748 2-Methylpropyl2,3,6-Trifluorophenyl 1749 3-Methylbutyl 2,3,6-Trifluorophenyl 17502-Methylpropyl 3-Chloro-4-phenyl 1751 3-Methylbutyl 3-Chloro-4-phenyl1752 2-Methylpropyl 2,4,5-Trifluorophenyl 1753 3-Methylbutyl2,4,5-Trifluorophenyl 1754 2-Methylpropyl 2,6-Difluorophenyl 17553-Methylbutyl 2,6-Difluorophenyl 1881 Butyl Phenyl 1882 2-MethylpropylPhenyl 1883 Pentyl Phenyl 1884 3-Methylbutyl Phenyl 1885 Butyl3-Methylphenyl 1886 2-Methylpropyl 3-Methylphenyl 1887 Pentyl3-Methylphenyl 1888 3-Methylbutyl 3-Methylphenyl 1889 2-Methylpropyl4-Methylphenyl 1890 3-Methylbutyl 4-Methylphenyl 1891 Butyl3-Fluorophenyl 1892 2-Methylpropyl 3-Fluorophenyl 1893 Pentyl3-Fluorophenyl 1894 3-Methylbutyl 3-Fluorophenyl 1895 2-Methylpropyl4-Fluorophenyl 1896 3-Methylbutyl 4-Fluorophenyl 1897 Butyl2-Fluorophenyl 1898 2-Methylpropyl 2-Fluorophenyl 1899 Pentyl2-Fluorophenyl 1900 3-Methylbutyl 2-Fluorophenyl 1901 2-Methylpropyl3,4-Dimethylphenyl 1902 Butyl 2-Chlorophenyl 1903 2-Methylpropyl2-Chlorophenyl 1904 Pentyl 2-Chlorophenyl 1905 3-Methylbutyl2-Chlorophenyl 1906 Butyl 3,4-Difluorophenyl 1907 2-Methylpropyl3,4-Difluorophenyl 1908 Pentyl 3,4-Difluorophenyl 1909 3-Methylbutyl3,4-Difluorophenyl 1910 Butyl 2,3-Difluorophenyl 1911 2-Methylpropyl2,3-Difluorophenyl 1912 Pentyl 2,3-Difluorophenyl 1913 3-Methylbutyl2,3-Difluorophenyl 1914 Butyl 2,5-Difluorophenyl 1915 2-Methylpropyl2,5-Difluorophenyl 1916 Pentyl 2,5-Difluorophenyl 1917 3-Methylbutyl2,5-Difluorophenyl 1918 2-Methylpropyl 2,4-Difluorophenyl 19193-Methylbutyl 2,4-Difluorophenyl 1920 2-Methylpropyl1,3-Benzodioxol-5-yl 1921 3-Methylbutyl 1,3-Benzodioxol-5-yl 19273-Methylbutyl 3-Iodo-4-methylphenyl 1963 2-Methylpropyl2-(2-Chlorophenyl) ethenyl 1964 Butyl 2-Thienyl 1965 Pentyl 2-Thienyl1966 3-Methylbutyl 2-Thienyl 1967 Pentyl 3-Thienyl 1968 3-Methylbutyl3-Thienyl 1969 3-Methylbutyl Benzyl 1970 Butyl 5-Methyl-2-thienyl 19712-Methylpropyl 5-Methyl-2-thienyl 1972 Pentyl 5-Methyl-2-thienyl 19733-Methylbutyl 5-Methyl-2-thienyl 1974 3-Methylbutyl 3-Fluorobenzyl 19753-Methylbutyl 3-Methoxybenzyl

EXAMPLE 26

For each compound, the definitions of R₂ and R₃ are specified in thefollowing table.

Compound No. R₂ R₃ 1250 Propyl 3-Iodophenyl 1616 2-Methylpropyl3-Chloro-4-fluorophenyl 1617 2-Methylpropyl 3-Bromophenyl 16183-Methylbutyl 3-Bromophenyl 1634 2-Methylpropyl 3-Bromo-4-methylphenyl1635 2-Methylpropyl 3-Bromo-4-fluorophenyl 1636 3-Methylbutyl3-Bromo-4-fluorophenyl 1637 2-Methylpropyl 3-Iodophenyl 16383-Methylbutyl 3-Bromo-4-fluorophenyl 1639 2-Methylpropyl Phenyl 16403-Methylbutyl Phenyl 1641 2-Methylpropyl 3-Methylphenyl 16423-Methylbutyl 3-Methylphenyl 1643 2-Methylpropyl 4-Methylphenyl 16442-Methylpropyl 3-Fluorophenyl 1645 3-Methylbutyl 3-Fluorophenyl 16462-Methylpropyl 4-Fluorophenyl 1647 2-Methylpropyl 2-Fluorophenyl 16483-Methylbutyl 2-Fluorophenyl 1649 2-Methylpropyl 3,4-Dimethylphenyl 16502-Methylpropyl 3-Fluoro-4-methylphenyl 1651 2-Methylpropyl3-Chlorophenyl 1652 3-Methylbutyl 3-Chlorophenyl 1674 2-Methylpropyl3-Iodo-4-methylphenyl 1675 2-Methylpropyl 5-Methyl-2-thienyl 16763-Methylbutyl 5-Methyl-2-thienyl 1677 3-Methylbutyl 3-Fluorobenzyl 17152-Methylpropyl 3-Chloro-4-methylphenyl 1716 2-Methylpropyl2,4,5-Trifluorophenyl 1874 Butyl 3,4-Dimethylphenyl 1875 2-Methylpropyl3,4-Dimethylphenyl 1876 3-Methylbutyl 3,4-Dimethylphenyl 18773-Methylbutyl 2,3-Dimethylphenyl 1878 2-Methylpropyl 2,5-Dimethylphenyl1879 3-Methylbutyl 2,5-Dimethylphenyl 1880 2-Methylpropyl1,3-Benzodioxol-5-yl 1976 3-Methylbutyl 3-Methoxybenzyl 2262 Benzyl3-Chlorophenyl 2282 Benzyl 5-Chloro-2-methoxyphenyl 2293 Benzyl3-Bromophenyl 2299 Benzyl 3-Iodophenyl

EXAMPLE 27

For each compound, the definitions of R₂ and R₃ are specified in thefollowing table.

Compound No. R₂ R₃ 1276 2-Methylpropyl Phenyl 1277 Pentyl Phenyl 12783-Methylbutyl Phenyl 1279 3-Methylbutyl 3-Methylphenyl 12802-Methylpropyl 4-Methylphenyl 1281 2-Methylpropyl 3-Fluorophenyl 12823-Methylbutyl 3-Fluorophenyl 1283 2-Methylpropyl 4-Fluorophenyl 1284Butyl 2-Fluorophenyl 1285 2-Methylpropyl 2-Fluorophenyl 1286 Pentyl2-Fluorophenyl 1287 3-Methylbutyl 2-Fluorophenyl 1288 2-Methylpropyl3-Methoxyphenyl 1289 3-Methylbutyl 3-Methoxyphenyl 1290 3-Methylbutyl4-Methoxyphenyl 1291 2-Methylpropyl 3-Fluoro-4-methylphenyl 12923-Methylbutyl 2-Fluoro-3-methylphenyl 1293 Butyl 3-Chlorophenyl 12942-Methylpropyl 3-Chlorophenyl 1295 Pentyl 3-Chlorophenyl 12963-Methylbutyl 3-Chlorophenyl 1297 2-Methylpropyl 3,4-Difluorophenyl 12982-Methylpropyl 2,3-Difluorophenyl 1299 3-Methylbutyl 2,3-Difluorophenyl1300 3-Methylbutyl 2,5-Difluorophenyl 1301 2-Methylpropyl1,3-Benzodioxol-5-yl 1302 2-Methylpropyl 1,3-Benzodioxol-5-yl 13863-Methylbutyl 5-Chloro-2-methoxyphenyl 1387 3-Methylbutyl 3-Bromophenyl1388 2-Methylpropyl 4-Bromophenyl 1389 2-Methylpropyl 5-Methyl-2-thienyl1390 3-Methylbutyl 5-Methyl-2-thienyl 1685 3-Methylbutyl2,3,6-Trifluorophenyl

EXAMPLE 28

For each compound, the definitions of R₂ and R₃ are specified in thefollowing table.

Compound No. R₂ R₃ 1303 Butyl Phenyl 1304 2-Methylpropyl Phenyl 1305Pentyl Phenyl 1306 3-Methylbutyl Phenyl 1307 Butyl 3-Methylphenyl 13082-Methylpropyl 3-Methylphenyl 1309 Pentyl 3-Methylphenyl 13103-Methylbutyl 3-Methylphenyl 1311 Butyl 4-Methylphenyl 13122-Methylpropyl 4-Methylphenyl 1313 3-Methylbutyl 4-Methylphenyl 13143-Methylbutyl 2-Methylphenyl 1315 Butyl 3-Fluorophenyl 13162-Methylpropyl 3-Fluorophenyl 1317 Pentyl 3-Fluorophenyl 13183-Methylbutyl 3-Fluorophenyl 1319 2-Methylpropyl 4-Fluorophenyl 13203-Methylbutyl 4-Fluorophenyl 1321 Butyl 2-Fluorophenyl 13222-Methylpropyl 2-Fluorophenyl 1323 Pentyl 2-Fluorophenyl 13243-Methylbutyl 2-Fluorophenyl 1325 2-Methylpropyl 4-Ethylphenyl 1326Butyl 3,4-Dimethylphenyl 1327 2-Methylpropyl 3,4-Dimethylphenyl 13283-Methylbutyl 3,4-Dimethylphenyl 1329 2-Methylpropyl 2,4-Dimethylphenyl1330 Butyl 3-Methoxyphenyl 1331 2-Methylpropyl 3-Methoxyphenyl 1332Pentyl 3-Methoxyphenyl 1333 3-Methylbutyl 3-Methoxyphenyl 1334 Butyl4-Methoxyphenyl 1335 2-Methylpropyl 4-Methoxyphenyl 1336 3-Methylbutyl4-Methoxyphenyl 1337 Pentyl 2-Methoxyphenyl 1338 3-Methylbutyl2-Methoxyphenyl 1339 Butyl 3-Fluoro-4-methylphenyl 1340 Pentyl3-Fluoro-4-methylphenyl 1341 3-Methylbutyl 3-Fluoro-4-methylphenyl 13423-Methylbutyl 3-Fluoro-2-methylphenyl 1343 Butyl 2-Fluoro-3-methylphenyl1344 2-Methylpropyl 2-Fluoro-3-methylphenyl 1345 Pentyl2-Fluoro-3-methylphenyl 1346 3-Methylbutyl 2-Fluoro-3-methylphenyl 1347Butyl 3-Chlorophenyl 1348 2-Methylpropyl 3-Chlorophenyl 1349 Pentyl3-Chlorophenyl 1350 3-Methylbutyl 3-Chlorophenyl 1351 2-Methylpropyl4-Chlorophenyl 1352 Pentyl 4-Chlorophenyl 1353 3-Methylbutyl4-Chlorophenyl 1354 Butyl 2-Chlorophenyl 1355 2-Methylpropyl2-Chlorophenyl 1356 Pentyl 2-Chlorophenyl 1357 3-Methylbutyl2-Chlorophenyl 1358 Butyl 3,4-Difluorophenyl 1359 2-Methylpropyl3,4-Difluorophenyl 1360 Pentyl 3,4-Difluorophenyl 1361 3-Methylbutyl3,4-Difluorophenyl 1362 Butyl 2,3-Difluorophenyl 1363 2-Methylpropyl2,3-Difluorophenyl 1364 Pentyl 2,3-Difluorophenyl 1365 3-Methylbutyl2,3-Difluorophenyl 1366 Butyl 2,5-Difluorophenyl 1367 2-Methylpropyl2,5-Difluorophenyl 1368 Pentyl 2,5-Difluorophenyl 1369 3-Methylbutyl2,5-Difluorophenyl 1370 Butyl 2,4-Difluorophenyl 1371 2-Methylpropyl2,4-Difluorophenyl 1372 Pentyl 2,4-Difluorophenyl 1373 3-Methylbutyl2,4-Difluorophenyl 1374 2-Methylpropyl 3-Ethoxyphenyl 1375 3-Methylbutyl3-Ethoxyphenyl 1376 Butyl 1,3-Benzodioxol-5-yl 1377 2-Methylpropyl1,3-Benzodioxol-5-yl 1378 Pentyl 1,3-Benzodioxol-5-yl 1379 3-Methylbutyl1,3-Benzodioxol-5-yl 1380 Butyl 4-Methylthio phenyl 1381 2-Methylpropyl4-Methylthio phenyl 1382 3-Methylbutyl 3-Fluoro-4-methoxyphenyl 1383Butyl 3-Chloro-4-fluorophenyl 1384 2-Methylpropyl3-Chloro-4-fluorophenyl 1385 3-Methylbutyl 3-Chloro-4-fluorophenyl 13913-Methylbutyl 3-Chloro-4-methoxyphenyl 1392 Pentyl5-Chloro-2-methoxyphenyl 1393 3-Methylbutyl 5-Chloro-2-methoxyphenyl1394 2-Methylpropyl 3,4-Dichlorophenyl 1395 3-Methylbutyl3,4-Dichlorophenyl 1396 Butyl 2,5-Dichlorophenyl 1397 2-Methylpropyl2,5-Dichlorophenyl 1398 Pentyl 2,5-Dichlorophenyl 1399 3-Methylbutyl2,5-Dichlorophenyl 1400 2-Methylpropyl 2,4-Dichlorophenyl 14013-Methylbutyl 2,4-Dichlorophenyl 1402 Butyl 3-Bromophenyl 14032-Methylpropyl 3-Bromophenyl 1404 Pentyl 3-Bromophenyl 14053-Methylbutyl 3-Bromophenyl 1406 2-Methylpropyl 4-Bromophenyl 14073-Methylbutyl 4-Bromophenyl 1408 3-Methylbutyl 2-Bromophenyl 14093-Methylbutyl 3-Bromo-4-methylphenyl 1410 Butyl 3-Bromo-4-fluorophenyl1411 2-Methylpropyl 3-Bromo-4-fluorophenyl 1412 Pentyl3-Bromo-4-fluorophenyl 1413 3-Methylbutyl 3-Bromo-4-fluorophenyl 1414Butyl 3-Iodophenyl 1415 2-Methylpropyl 3-Iodophenyl 1416 Pentyl3-Iodophenyl 1417 3-Methylbutyl 3-Iodophenyl 1418 Butyl5-Methyl-2-thienyl 1419 2-Methylpropyl 5-Methyl-2-thienyl 1420 Pentyl5-Methyl-2-thienyl 1421 3-Methylbutyl 5-Methyl-2-thienyl 14223-Methylbutyl 3-Fluorobenzyl 1423 3-Methylbutyl 3-Methoxybenzyl 14243-Methylbutyl 2-Methoxybenzyl 1686 2-Methylpropyl 2,4,6-Trifluorophenyl1687 Butyl 2,3,6-Trifluorophenyl 1688 2-Methylpropyl2,3,6-Trifluorophenyl 1689 Pentyl 2,3,6-Trifluorophenyl 16903-Methylbutyl 2,3,6-Trifluorophenyl 1691 3-Methylbutyl2,5-Dimethyl-3-furyl 1692 Butyl 4,5-Dimethyl-2-furyl 1693 2-Methylpropyl4,5-Dimethyl-2-furyl 1694 Pentyl 4,5-Dimethyl-2-furyl 1695 3-Methylbutyl4,5-Dimethyl-2-furyl 1696 2-Methylpropyl 2-(3-Thienyl)ethenyl 1697Pentyl 3-Chloro-2-thienyl 1698 3-Methylbutyl 3-Chloro-2-thienyl 16992-Methylpropyl 5-Methylthio-2-thienyl 1700 3-Methylbutyl5-Methylthio-2-thienyl 1721 Butyl 3-Chloro-4-methylphenyl 17222-Methylpropyl 3-Chloro-4-methylphenyl 1723 3-Methylbutyl3-Chloro-4-methylphenyl 1724 2-Methylpropyl 2,4,5-Trichlorophenyl

EXAMPLE 29

For each compound, the definitions of R₂ and R₃ are specified in thefollowing table.

Compound No. R₂ R₃ 1468 Methyl Phenyl 1469 Allyl Phenyl 1470 PropylPhenyl 1471 Methyl 3-Methylphenyl 1472 Allyl 3-Methylphenyl 1473 Propyl3-Methylphenyl 1474 Propyl 4-Methylphenyl 1475 Methyl 3-Fluorophenyl1476 Allyl 3-Fluorophenyl 1477 Propyl 3-Fluorophenyl 1478 Propyl4-Fluorophenyl 1479 Methyl 2-Fluorophenyl 1480 Allyl 2-Fluorophenyl 1481Propyl 2-Fluorophenyl 1482 Propyl 3,4-Dimethylphenyl 1483 Propyl3-Methoxyphenyl 1484 Propyl 3-Fluoro-4-methylphenyl 1485 Allyl3-Chlorophenyl 1486 Propyl 3-Chlorophenyl 1487 Propyl 2-Chlorophenyl1488 Propyl 3,4-Difluorophenyl 1489 Methyl 2,3-Difluorophenyl 1490Propyl 2,3-Difluorophenyl 1491 Methyl 2,5-Difluorophenyl 1492 Allyl2,5-Difluorophenyl 1493 Propyl 2,5-Difluorophenyl 1494 Propyl2,4-Difluorophenyl 1495 Propyl 1,3-Benzodioxol-5-yl 1496 Propyl3-Chloro-4-fluorophenyl 1497 Methyl 5-Chloro-2-methoxyphenyl 1498 Methyl3-Trifluoromethylphenyl 1499 Propyl 3-Trifluoromethylphenyl 1500 Methyl2,5-Dichlorophenyl 1501 Propyl 2,5-Dichlorophenyl 1502 Methyl3-Bromophenyl 1503 Allyl 3-Bromophenyl 1504 Propyl 3-Bromophenyl 1505Propyl 3-Bromo-4-methylphenyl 1506 Methyl 3-Bromo-4-fluorophenyl 1507Allyl 3-Bromo-4-fluorophenyl 1508 Propyl 3-Bromo-4-fluorophenyl 1509Methyl 3-Iodophenyl 1510 Ethyl 3-Iodophenyl 1511 Allyl 3-Iodophenyl 1512Propyl 3-Iodophenyl 1513 Propyl 5-Methyl-2-thienyl 1514 Propyl3-Fluorobenzyl 1515 Methyl 5-Ethoxy-2-thienyl

EXAMPLE 30

For each compound, the definitions of R₂ and R₃ are specified in thefollowing table.

Compound No. R₂ R₃ 1717 Propyl 3-Chloro-4-methylphenyl 1718 Propyl2,4,5-Trifluorophenyl 2237 Benzyl Phenyl 2240 Benzyl 3-Fluorophenyl 2241Benzyl 4-Fluorophenyl 2244 Benzyl 2-Fluorophenyl 2246 Benzyl3,4-Dimethylphenyl 2247 Benzyl 3,5-Dimethylphenyl 2248 Benzyl2,3-Dimethylphenyl 2249 Benzyl 2,5-Dimethylphenyl 2250 Benzyl2,4-Dimethylphenyl 2252 Benzyl 3-Methoxyphenyl 2255 Benzyl2-Methoxyphenyl 2256 Benzyl 3-Fluoro-4-methylphenyl 2259 Benzyl5-Fluoro-2-methylphenyl 2263 Benzyl 3-Chlorophenyl 2264 Benzyl4-Chlorophenyl 2265 Benzyl 2-Chlorophenyl 2267 Benzyl 3,4-Difluorophenyl2270 Benzyl 2,3-Difluorophenyl 2273 Benzyl 2,5-Difluorophenyl 2274Benzyl 2,4-Difluorophenyl 2275 Benzyl 3-Ethoxyphenyl 2276 Benzyl1,3-Benzodioxol-5-yl 2277 Benzyl 4-Chloro-3-methylphenyl 2278 Benzyl3-Chloro-4-fluorophenyl 2279 Benzyl 3,4,5-Trifluorophenyl 2280 Benzyl2,5-Dimethoxyphenyl 2283 Benzyl 5-Chloro-2-methoxyphenyl 2284 Benzyl4-Chloro-2-methoxyphenyl 2285 Benzyl 3-Trifluoromethylphenyl 2286 Benzyl2-Trifluoromethylphenyl 2287 Benzyl 3,4-Dichlorophenyl 2288 Benzyl2,3-Dichlorophenyl 2290 Benzyl 2,5-Dichlorophenyl 2291 Benzyl2,4-Dichlorophenyl 2294 Benzyl 3-Bromophenyl 2296 Benzyl 2-Bromophenyl2297 Benzyl 3-Bromo-4-fluorophenyl 2300 Benzyl 3-Iodophenyl 2301 Benzyl2-Methoxyphenyl 2303 Benzyl 2,5-Dimethylpyrrol-3-yl 2308 Benzyl2,3,6-Trifluorphenyl 2309 3-Methylbutyl 2-Chloro-6-fluorophenyl 23253-Methylbutyl 3-(Methylamino methyl)phenyl 2326 3-Methylbutyl3-(Ethylamino methyl)phenyl 2327 3-Methylbutyl 3-(allylaminomethyl)phenyl 2328 3-Methylbutyl 3-(propylamino methyl)phenyl 23293-Methylbutyl 3-[(Cyclopropyl methyl)amino methyl]phenyl 23303-Methylbutyl 3-(butylamino methyl)phenyl 2331 3-Methylbutyl3-[(2-Methylpropyl) amino methyl]phenyl 2332 3-Methylbutyl3-(Pentylamino methyl)phenyl 2333 3-Methylbutyl 3-[(3-Methylbutyl) aminomethyl]phenyl 2334 3-Methylbutyl 3-[(2-Methylbutyl) amino methyl]phenyl2335 3-Methylbutyl 3-(Hexylamino methyl)phenyl 2336 3-Methylbutyl3-(Cyclopropyl amino methyl)phenyl 2337 3-Methylbutyl 3-[(1-Methylethyl)aminomethyl] phenyl 2338 3-Methylbutyl 3-(Cyclobutyl amino methyl)phenyl2339 3-Methylbutyl 3-[(1-Methylpropyl) aminomethyl] phenyl 23403-Methylbutyl 3-[(1,1-Dimethylethyl) aminomethyl] phenyl 23413-Methylbutyl 3-(Cyclopentyl amino methyl)phenyl 2342 3-Methylbutyl3-[(1-Methylbutyl) aminomethyl] phenyl 2343 3-Methylbutyl3-[(1,2-Dimethylpropyl) aminomethyl] phenyl 2344 3-Methylbutyl3-[(1-Ethylpropyl) aminomethyl] phenyl 2345 3-Methylbutyl3-[(1,1-Dimethylpropyl) aminomethyl] phenyl 2346 3-Methylbutyl3-(Cyclohexyl amino methyl)phenyl 2352 3-Methylbutyl 3-(Piperidylmethyl)phenyl 2353 3-Methylbutyl 3-(Morpholin-4-yl methyl)phenyl 23543-Methylbutyl 3-(Azaperhydroepinylmethyl) phenyl 2355 3-Methylbutyl3-(Azaperhydroocinylmethyl) phenyl 2356 3-Methylbutyl3-(2-1,2,3,4-Teterahydro isoquinolinyl methyl) phenyl 2357 3-Methylbutyl3-(Methylpropyl aminomethyl) phenyl 2358 3-Methylbutyl 3-(i-propylethylaminomethyl) phenyl 2359 3-Methylbutyl 3-(Diethyl aminomethyl) phenyl2360 3-Methylbutyl 3-(Butylethyl aminomethyl) phenyl 2361 3-Methylbutyl3-[(Cyclopropyl methyl)propyl aminomethyl] phenyl 2362 3-Methylbutyl3-(Hexylmethyl aminomethyl) phenyl 2363 3-Methylbutyl 3-(Dibutylaminomethyl) phenyl 2370 3-Methylbutyl 3-[(1-methylethyl) methylaminomethyl] phenyl 2371 3-Methylbutyl 3-[(2-Methyl piperidyl)methyl]phenyl 2372 3-Methylbutyl 3-[Ethyl(2-Methylprop-2-enyl)aminomethyl]phenyl 2373 3-Methylbutyl 3-[(2-Ethyl piperidyl) methyl]phenyl2374 3-Methylbutyl 3-(Cyclohexyl ethyl aminomethyl) phenyl 23753-Methylbutyl 3-[bis(2-Methoxyethyl) aminomethyl] phenyl 23763-Methylbutyl 3-[(3,3,5-Trimethylazaperhydroepinyl) methyl]phenyl 23773-Methylbutyl 3-[(8-Aza-1,4-dioxaspiro[4.5]dec-8- yl)methyl] phenyl 23783-Methylbutyl 3-(Dipentylamino methyl)phenyl 2379 3-Methylbutyl3-(Dihexylamino methyl)phenyl

EXAMPLE 31

For each compound, the definitions of R₂ and R₃ are specified in thefollowing table.

Compound No. R₂ R₃ 2004 2-Methylpropyl 2-(4-Chlorophenyl) ethenyl

EXAMPLE 32

For each compound, the definitions of R₂ and R₃ are specified in thefollowing table.

Compound No. R₂ R₃ 2020 Methyl 3-Thienyl 2021 i-Propyl3-Methyl-2-thienyl 2022 Methyl 4-Methylbenzyl 2023 Methyl 2-Methylbenzyl2024 Methyl 3-Fluorobenzyl

EXAMPLE 33

For each compound, the definitions of R₂ and R₃ are specified in thefollowing table.

Compound No. R₄ R₃ 2025 3-Pyrrolinyl 2,5-Difluorophenyl 20263-Pyrrolinyl 3-Fluorophenyl 2027 Pyrrolidinyl 2,5-Difluorophenyl 2028Pyrrolidinyl 3-Fluorophenyl 2029 1,2,5,6-Tetrahydro 2,5-Difluorophenylpyridyl 2030 1,2,5,6-Tetrahydro 3-Fluorophenyl pyridyl 2031 Piperidyl2,5-Difluorophenyl 2032 Piperidyl 3-Fluorophenyl 2039 Morpholinyl2,5-Difluorophenyl 2040 Morpholinyl 3-Fluorophenyl 2043 4-Methyl2,5-Difluorophenyl piperidyl 2044 4-Methyl 3-Fluorophenyl piperidyl 2046Azaperhydro 2,5-Difluorophenyl epinyl 2047 Azaperhydro 3-FluorophenylEpinyl 2049 1,4-Thiazaper 2,5-Difluorophenyl hydroin-4-yl 20501,4-Thiazaper 3-Fluorophenyl hydroin-4-yl 2053 3,3-dimethyl2,5-Difluorophenyl piperidyl 2054 3,3-dimethyl 3-Fluorophenyl piperidyl2057 Azaperhydro 2,5-Difluorophenyl ocinyl 2058 Azaperhydro3-Fluorophenyl Ocinyl 2061 2-(1,2,3,4-Tetrahydroiso 2,5-Difluorophenylquinolyl) 2062 2-(1,2,3,4-Tetrahydroiso 3-Fluorophenyl quinolyl) 2065Methylprop-2-enylamino 2,5-Difluorophenyl 2066 Methylprop-2-enylamino3-Fluorophenyl 2068 Diethylamino 2,5-Difluorophenyl 2069 Diethylamino3-Fluorophenyl 2072 Methylpropyl 2,5-Difluorophenyl amino 2073Methylpropyl 3-Fluorophenyl Amino 2076 Butylmethyl 2,5-Difluorophenylamino 2077 Butylmethyl 3-Fluorophenyl Amino 2080 i-Propylethyl2,5-Difluorophenyl amino 2081 i-Propylethyl 3-Fluorophenyl amino 2084Diallylamino 2,5-Difluorophenyl 2085 Diallylamino 3-Fluorophenyl 2088Dipropylamino 2,5-Difluorophenyl 2089 Dipropylamino 3-Fluorophenyl 2092Butylethyl 2,5-Difluorophenyl Amino 2093 Butylethyl 3-Fluorophenyl Amino2096 (Cyclo 2,5-Difluorophenyl propylmethyl) propylamino 2097 (Cyclo3-Fluorophenyl propylmethyl) propylamino 2100 Hexylmethyl2,5-Difluorophenyl amino 2101 Hexylmethyl 3-Fluorophenyl Amino 2104Dibutylamino 2,5-Difluorophenyl 2105 Dibutylamino 3-Fluorophenyl 2107Methylamino 2,5-Difluorophenyl 2108 Methylamino 3-Fluorophenyl 2110Ethylamino 2,5-Difluorophenyl 2111 Ethylamino 3-Fluorophenyl 2114Allylamino 2,5-Difluorophenyl 2115 Allylamino 3-Fluorophenyl 2118Propylamino 2,5-Difluorophenyl 2119 Propylamino 3-Fluorophenyl 2122(Cyclopropyl 2,5-Difluorophenyl methyl)amino 2123 (Cyclopropyl3-Fluorophenyl methyl)amino 2126 Butyl 2,5-Difluorophenyl 2127 Butyl3-Fluorophenyl 2130 (2-Methylpropyl) 2,5-Difluorophenyl amino 2131(2-Methylpropyl) 3-Fluorophenyl amino 2134 Pentylamino2,5-Difluorophenyl 2135 Pentylamino 3-Fluorophenyl 2138 (3-Methylbutyl)2,5-Difluorophenyl amino 2139 (3-Methylbutyl) 3-Fluorophenyl amino 2141(2-Methylbutyl) 2,5-Difluorophenyl amino 2142 (2-Methylbutyl)3-Fluorophenyl amino 2145 Hexylamino 2,5-Difluorophenyl 2146 Hexylamino3-Fluorophenyl 2148 [2-(Dimethyl 2,5-Difluorophenyl amino)ethyl] amino2149 [2-(Dimethyl 3-Fluorophenyl amino)ethyl] amino 2150 [3-(Dimethyl2,5-Difluorophenyl amino)propyl] amino 2151 [3-(Dimethyl 3-Fluorophenylamino)propyl] amino 2153 (2-Pyrrolidinyl 2,5-Difluorophenyl ethyl)amino2154 (2-Pyrrolidinyl 3-Fluorophenyl ethyl)amino 2157 [2-(Diethyl2,5-Difluorophenyl amino)ethyl] amino 2158 [2-(Diethyl 3-Fluorophenylamino)ethyl] amino 2161 (2-Piperidyl 2,5-Difluorophenyl ethyl)amino 2162(2-Piperidyl 3-Fluorophenyl ethyl)amino 2164 [2-(1-Methyl2,5-Difluorophenyl pyrrolidin-2-yl)ethyl]amino 2165 [2-(1-Methyl3-Fluorophenyl pyrrolidin-2-yl)ethyl]amino 2168 [2-(Diethyl2,5-Difluorophenyl amino)propyl] amino 2169 [2-(Diethyl 3-Fluorophenylamino)propyl] amino 2172 (2-Morpholin-4-yl 2,5-Difluorophenylethyl)amino 2173 (2-Morpholin-4-yl 3-Fluorophenyl ethyl)amino 2176(3-Morpholin-4-yl 2,5-Difluorophenyl propyl)amino 2177 (3-Morpholin-4-yl3-Fluorophenyl propyl)amino 2180 [3-(2-Methyl 2,5-Difluorophenylpiperidyl) propyl]amino 2181 [3-(2-Methyl 3-Fluorophenyl piperidyl)propyl]amino 2184 [3-(2-Oxo 2,5-Difluorophenyl pyrrolidinyl)propyl]amino 2185 [3-(2-Oxo 3-Fluorophenyl pyrrolidinyl) propyl]amino

EXAMPLE 34

For each compound, the definitions of R₂ and R₃ are specified in thefollowing table.

Compound No. R₄ R₃ 2033 Pyrrolidinyl 2,5-Difluorophenyl 2034Pyrrolidinyl 3-Fluorophenyl 2035 1,2,5,6-Tetrahydro 2,5-Difluorophenylpyridyl 2036 1,2,5,6-Tetrahydro 3-Fluorophenyl pyridyl 2037 Piperidyl2,5-Difluorophenyl 2038 Morpholinyl 3-Fluorophenyl 2041 4-Methyl2,5-Difluorophenyl piperidyl 2042 4-Methyl 3-Fluorophenyl piperidyl 2045Azaperhydro 3-Fluorophenyl Epinyl 2048 1,4-Thiazaper 3-Fluorophenylhydroin-4-yl 2051 3,3-dimethyl 2,5-Difluorophenyl piperidyl 20523,3-dimethyl 3-Fluorophenyl piperidyl 2055 Azaperhydro2,5-Difluorophenyl ocinyl 2056 Azaperhydro 3-Fluorophenyl Ocinyl 20592-(1,2,3,4- 2,5-Difluorophenyl Tetrahydroiso quinolyl) 2060 2-(1,2,3,4-3-Fluorophenyl Tetrahydroiso quinolyl) 2063 Methylprop-2-2,5-Difluorophenyl enylamino 2064 Methylprop-2- 3-Fluorophenyl enylamino2067 Diethylamino 3-Fluorophenyl 2070 Methylpropyl 2,5-Difluorophenylamino 2071 Methylpropyl 3-Fluorophenyl Amino 2074 Butylmethyl2,5-Difluorophenyl amino 2075 Butylmethyl 3-Fluorophenyl Amino 2078i-Propylethyl 2,5-Difluorophenyl amino 2079 i-Propylethyl 3-Fluorophenylamino 2082 Diallylamino 2,5-Difluorophenyl 2083 Diallylamino3-Fluorophenyl 2086 Dipropylamino 2,5-Difluorophenyl 2087 Dipropylamino3-Fluorophenyl 2090 Butylethyl 2,5-Difluorophenyl Amino 2091 Butylethyl3-Fluorophenyl Amino 2094 (Cyclo 2,5-Difluorophenyl propylmethyl)propylamino 2095 (Cyclo 3-Fluorophenyl propylmethyl) propylamino 2098Hexylmethyl 2,5-Difluorophenyl Amino 2099 Hexylmethyl 3-FluorophenylAmino 2102 Dibutylamino 2,5-Difluorophenyl 2103 Dibutylamino3-Fluorophenyl 2106 Methylamino 3-Fluorophenyl 2109 Ethylamino3-Fluorophenyl 2112 Allylamino 2,5-Difluorophenyl 2113 Allylamino3-Fluorophenyl 2116 Propylamino 2,5-Difluorophenyl 2117 Propylamino3-Fluorophenyl 2120 (Cyclopropyl 2,5-Difluorophenyl methyl)amino 2121(Cyclopropyl 3-Fluorophenyl methyl)amino 2124 Butyl 2,5-Difluorophenyl2125 Butyl 3-Fluorophenyl 2128 (2-Methylpropyl) 2,5-Difluorophenyl amino2129 (2-Methylpropyl) 3-Fluorophenyl amino 2132 Pentylamino2,5-Difluorophenyl 2133 Pentylamino 3-Fluorophenyl 2136 (3-Methylbutyl)2,5-Difluorophenyl amino 2137 (3-Methylbutyl) 3-Fluorophenyl amino 2140(2-Methylbutyl) 3-Fluorophenyl amino 2143 Hexylamino 2,5-Difluorophenyl2144 Hexylamino 3-Fluorophenyl 2152 (2-Pyrrolidinyl 3-Fluorophenylethyl)amino 2155 [2-(Diethyl 2,5-Difluorophenyl amino)ethyl] amino 2156[2-(Diethyl 3-Fluorophenyl amino)ethyl] amino 2159 (2-Piperidyl2,5-Difluorophenyl ethyl)amino 2160 (2-Piperidyl 3-Fluorophenylethyl)amino 2163 [2-(1-Methyl 3-Fluorophenyl pyrrolidin-2-yl)ethyl]amino 2166 [2-(Diethyl 2,5-Difluorophenyl amino)propyl] amino2167 [2-(Diethyl 3-Fluorophenyl amino)propyl] amino 2170(2-Morpholin-4-yl 2,5-Difluorophenyl ethyl)amino 2171 (2-Morpholin-4-yl3-Fluorophenyl ethyl)amino 2174 (3-Morpholin-4-yl 2,5-Difluorophenylpropyl)amino 2175 (3-Morpholin-4-yl 3-Fluorophenyl propyl)amino 2178[3-(2-Methyl 2,5-Difluorophenyl piperidyl) propyl]amino 2179[3-(2-Methyl 3-Fluorophenyl piperidyl) propyl]amino 2182 [3-(2-Oxo2,5-Difluorophenyl pyrrolidinyl) propyl]amino 2183 [3-(2-Oxo3-Fluorophenyl pyrrolidinyl) propyl]amino

EXAMPLE 35

For each compound, the definitions of R₂ and R₃ are specified in thefollowing table.

Compound No. R₂ R₃ 2147 3-Methylbutyl 3-Chlorophenyl 2219 3-Methylbutyl3-Trifluoromethylphenyl 2220 Butyl 3-Bromophenyl 2221 2-Methylpropyl3-Bromophenyl 2222 3-Methylbutyl 3-Bromophenyl

EXAMPLE 36

For each compound, the definitions of R₂ and R₃ are specified in thefollowing table.

Compound No. R₂ R₃ 2186 Butyl 2,5-Dimethoxyphenyl 2187 2-Methylpropyl2,5-Dimethoxyphenyl 2188 3-Methylbutyl 2,5-Dimethoxyphenyl 2189 Butyl3-Chloro-4-methoxyphenyl 2190 2-Methylpropyl 3-Chloro-4-methoxyphenyl2191 3-Methylbutyl 3-Chloro-4-methoxyphenyl 2192 Butyl5-Chloro-2-methoxyphenyl 2193 2-Methylpropyl 5-Chloro-2-methoxyphenyl2194 3-Methylbutyl 5-Chloro-2-methoxyphenyl 2195 2-Methylpropyl4-Chloro-2-methoxyphenyl 2196 Butyl 3-Trifluoromethylphenyl 21972-Methylpropyl 3-Trifluoromethylphenyl 2198 3-Methylbutyl3-Trifluoromethylphenyl 2199 Butyl 2-Trifluoromethylphenyl 22003-Methylbutyl 2-Trifluoromethylphenyl 2201 Butyl 3,4-Dichlorophenyl 22022-Methylpropyl 3,4-Dichlorophenyl 2203 3-Methylbutyl 3,4-Dichlorophenyl2204 Butyl 2,5-Dichlorophenyl 2205 2-Methylpropyl 2,5-Dichlorophenyl2206 Pentyl 2,5-Dichlorophenyl 2207 3-Methylbutyl 2,5-Dichlorophenyl2208 Butyl 2,4-Dichlorophenyl 2209 2-Methylpropyl 2,4-Dichlorophenyl2210 3-Methylbutyl 2,4-Dichlorophenyl 2211 Butyl 3-Bromophenyl 22122-Methylpropyl 3-Bromophenyl 2213 Pentyl 3-Bromophenyl 22143-Methylbutyl 3-Bromophenyl 2215 2-Methylpropyl 4-Bromophenyl 2216 Butyl2-Bromophenyl 2217 2-Methylpropyl 2-Bromophenyl 2218 3-Methylbutyl2-Bromophenyl 2223 2-Methylpropyl 3-Phenoxyphenyl 2224 2-Methylpropyl4-Phenoxyphenyl 2225 2-Methylpropyl 3-Bromo-4-methylphenyl 2226 Pentyl3-Bromo-4-methylphenyl 2227 3-Methylbutyl 3-Bromo-4-methylphenyl 2228Butyl 3-Bromo-4-methylphenyl 2229 2-Methylpropyl 3-Bromo-4-methylphenyl2230 Pentyl 3-Bromo-4-methylphenyl 2231 3-Methylbutyl3-Bromo-4-methylphenyl 2232 Butyl 3-Iodophenyl 2233 2-Methylpropyl3-Iodophenyl 2234 Pentyl 3-Iodophenyl 2235 3-Methylbutyl 3-Iodophenyl2236 2-Methylpropyl 4-Iodophenyl 2310 2-Methylpropyl 2,3,5,6-Tetrafluorophenyl 2311 2-Methylpropyl 2,4,6-Trifluorophenyl 2312 Butyl2,3,6-Trifluorophenyl 2313 2-Methylpropyl 2,3,6-Trifluorophenyl 2314Pentyl 2,3,6-Trifluorophenyl 2315 3-Methylbutyl 2,3,6-Trifluorophenyl2316 Butyl 3-Chloro-6-fluorophenyl 2317 Pentyl 3-Chloro-6-fluorophenyl2318 3-Methylbutyl 3-Chloro-6-fluorophenyl 2319 Butyl 2-Fluoro-6-trifluoromethylphenyl

EXAMPLE 37

For each compound, the definitions of R₂ and R₃ are specified in thefollowing table.

Compound No. R₂ R₃ 2304 2-Methylpropyl 5-Methyl-2-thienyl

EXAMPLE 38

For each compound, the definitions of R₂ and R₃ are specified in thefollowing table.

Compound No. R₂ R₃ 2380 2-Methylpropyl 2,4-Difluorophenyl 23812-Methylpropyl 2H-Benzo[d]1,3-dioxolane 2382 2-Methylpropyl3-Chloro-4-methylphenyl

EXAMPLE 39

For each compound, the definitions of R₂ and R₃ are specified in thefollowing table.

Compound No. R₂ R₃ 2390 2-Methylpropyl 5-Methyl-2-thienyl

EXAMPLE 40

For each compound, the definitions of R₂ and R₃ are specified in thefollowing table.

Compound No. R₂ R₃ 2383 2-Methylpropyl 3-Chloro-4-methylphenyl 23842-Methylpropyl 2,4-Difluorophenyl 2385 2-Methylpropyl2H-Benzo[d]1,3-dioxolane

EXAMPLE 41

For each compound, the definitions of R₂ and R₃ are specified in thefollowing table.

Compound No. R₂ R₃ 2389 Pentyl 3-Fluoro-4-methylphenyl

EXAMPLE 42 Assay for GABA_(A) Receptor Binding

The following assay is a standard assay for GABA_(A) receptor binding.

The high affinity and high selectivity of compounds of this inventionfor the benzodiazepine site of the GABA_(A) receptor is confirmed usingthe binding assay described in Thomas and Tallman (J. Bio. Chem. 1981;156:9838-9842, and J. Neurosci. 1983; 3:433-440).

Rat cortical tissue is dissected and homogenized in 25 volumes (w/v) ofBuffer A (0.05 M Tris HCl buffer, pH 7.4 at 4° C.). The tissuehomogenate is centrifuged in the cold (4° C.) at 20,000×g for 20minutes. The supernatant is decanted, the pellet rehomogenized in thesame volume of buffer, and centrifuged again at 20,000×g. Thesupernatant of this centrifugation step is decanted and the pelletstored at −20° C. overnight. The pellet is then thawed and resuspendedin 25 volumes of Buffer A (original wt/vol), centrifuged at 20,000×g andthe supernatant decanted. This wash step is repeated once. The pellet isfinally resuspended in 50 volumes of Buffer A.

Incubations containi 100 l of tissue homogenate, 100 l of radioligand,(0.5 nM ³H-Ro15-1788 [³H-Flumazenil], specific activity 80 Ci/mmol), andtest compound or control (see below), and are brought to a total volumeof 500 l with Buffer A. Incubations are carried for 30 min at 4° C. andthen rapidly filtered through Whatman GFB filters to separate free andbound ligand. Filters are washed twice with fresh Buffer A and countedin a liquid scintillation counter. Nonspecific binding (control) isdetermined by displacement of ³H Ro15-1788 with 10 M Diazepam (ResearchBiochemicals International, Natick, Mass.). Data were collected intriplicate, averaged, and percent inhibition of total specific binding(Total Specific Binding=Total−Nonspecific) was calculated for eachcompound.

A competition binding curve is obtained with up to 11 points spanningthe compound concentration range from 10⁻¹²M to 10⁻⁵M obtained per curveby the method described above for determining percent inhibition. K_(i)values are calculated according the Cheng-Prussof equation. When testedin this assay compounds of the invention exihibit K_(i) values of lessthan 1 uM, preferred compounds of the invention have K_(i) values ofless than 500 nM and more compounds of the invention have K_(i) valuesof less than 100 nM.

EXAMPLE 43

Assay for GABA_(A) Receptor Functional Activity

Electrophysiology

The following assay is used to determine if a compound of the inventionact as an agonist, an antagonist, or an inverse agonist at thebenzodiazepine site of the GABA_(A) receptor.

Assays are carried out as described in White and Gurley (NeuroReport 6:1313-1316, 1995) and White, Gurley, Hartnett, Stirling, and Gregory(Receptors and Channels 3: 1-5, 1995) with modifications.Electrophysiological recordings are carried out using the two electrodevoltage-clamp technique at a membrane holding potential of −70 mV.Xenopus Laevis oocytes are enzymatically isolated and injected withnon-polyadenylated cRNA mixed in a ratio of 4:1:4 for, and _(subunits),respectively. Of the nine combinations of, and subunits described in theWhite et al. publications, preferred combinations are ₁ ₂ ₂,_(2 3 2, 3 3 2,) and _(5 3 2.) Preferably all of the subunit cRNAs ineach combination are human clones or all are rat clones. The sequence ofeach of these cloned subunits is available from GENBANK, e.g., human ₁,GENBANK accession no. X14766, human ₂, GENBANK accession no. A28100;human ₃, GENBANK accession no. A28102; human ₅, GENBANK accession no.A28104; human ₂, GENBANK accession no. M82919; human ₃, GENBANKaccession no. Z20136; human ₂, GENBANK accession no. X15376; rat ₁,GENBANK accession no. L08490, rat ₂, GENBANK accession no. L08491; rat₃, GENBANK accession no. L08492; rat ₅, GENBANK accession no. L08494;rat ₂, GENBANK accession no. X15467; rat ₃, GENBANK accession no.X15468; and rat ₂, GENBANK accession no. L08497. For each subunitcombination, sufficient message for each constituent subunit is injectedto provide current amplitudes of >10 nA when 1 μM GABA is applied.

Compounds are evaluated against a GABA concentration that evokes <10% ofthe maximal evokable GABA current (e.g. 1 M-9 M). Each oocyte is exposedto increasing concentrations of compound in order to evaluate aconcentration/effect relationship. Compound efficacy is calculated as apercent-change in current amplitude: 100*((Ic/I)−1), where Ic is theGABA evoked current amplitude observed in the presence of test compoundand I is the GABA evoked current amplitude observed in the absence ofthe test compound.

Specificity of a compound for the benzodiazepine site is determinedfollowing completion of a concentration/effect curve. After washing theoocyte sufficiently to remove previously applied compound, the oocyte isexposed to GABA+1 μM R₀₁₅-1788, followed by exposure to GABA+1 μMRO15-1788+test compound. Percent change due to addition of compound iscalculated as described above. Any percent change observed in thepresence of RO15-1788 is subtracted from the percent changes in currentamplitude observed in the absence of 1 μM R₀₁₅-1788. These net valuesare used for the calculation of average efficacy and EC₅₀ values bystandard methods. To evaluate average efficacy and EC₅₀ values, theconcentration/effect data are averaged across cells and fit to thelogistic equation.

EXAMPLE 44

Preparation of Radiolabeled Probe Compounds of the Invention

The compounds of the invention are prepared as radiolabeled probes bycarrying out their synthesis using precursors comprising at least oneatom that is a radioisotope. The radioisotope is preferably selectedfrom of at least one of carbon (preferably ¹⁴C), hydrogen (preferably³H), sulfur (preferably ³⁵S), or iodine (preferably ¹²⁵I). Suchradiolabeled probes are conveniently synthesized by a radioisotopesupplier specializing in custom synthesis of radiolabeled probecompounds. Such suppliers include Amersham Corporation, ArlingtonHeights, Ill.; Cambridge Isotope Laboratories, Inc. Andover, Mass.; SRIInternational, Menlo Park, Calif.; Wizard Laboratories, West Sacramento,Calif.; ChemSyn Laboratories, Lexena, Kans.; American RadiolabeledChemicals, Inc., St. Louis, Mo.; and Moravek Biochemicals Inc., Brea,Calif.

Tritium labeled probe compounds are also conveniently preparedcatalytically via platinum-catalyzed exchange in tritiated acetic acid,acid-catalyzed exchange in tritiated trifluoroacetic acid, orheterogeneous-catalyzed exchange with tritium gas. Such preparations arealso conveniently carried out as a custom radiolabeling by any of thesuppliers listed in the preceding paragraph using the compound of theinvention as substrate. In addition, certain precursors may be subjectedto tritium-halogen exchange with tritium gas, tritium gas reduction ofunsaturated bonds, or reduction using sodium borotritide, asappropriate.

EXAMPLE 45 Use of Compounds of the Invention as Probes for GABA_(A)Receptors in Cultured Cells and Tissue Samples

Receptor autoradiography (receptor mapping) of NK-3 or GABA_(A)receptors in cultured cells or tissue samples is carried out in vitro asdescribed by Kuhar in sections 8.1.1 to 8.1.9 of Current Protocols inPharmacology (1998) John Wiley & Sons, New York, using radiolabeledcompounds of the invention prepared as described in the precedingExample.

The invention and the manner and process of making and using it, are nowdescribed in such full, clear, concise and exact terms as to enable anyperson skilled in the art to which it pertains, to make and use thesame. It is to be understood that the foregoing describes preferredembodiments of the present invention and that modifications may be madetherein without departing from the spirit or scope of the presentinvention as set forth in the claims. To particularly point out anddistinctly claim the subject matter regarded as invention, the followingclaims conclude this specification.

1. A method for localizing GABA_(A) receptors in a tissue samplecomprising: a) contacting the sample in vitro with a detectably-labeledcompound under conditions that permit binding of the compound toGABA_(A) receptors, wherein said compound has the formula:

or pharmaceutically acceptable salts thereof wherein: W represents

where Z is O, or S; R₁ represents phenyl, C₁-C₆ alkyl, cyclopentyl,cyclohexyl, benzyl, 3-fluorobenzyl, or cyclopropylmethyl; R₂ representshydroxyl; C₁-C₆ alkyl or C₁-C₆ alkoxy, each of which are optionallysubstituted with amino, mono or di(C₁-C₆) alkylamino, a C₅-C₇heterocycloalkyl group where the heteroatom is nitrogen and the nitrogenis attached to the parent alkyl portion; O(CH₂)_(n)CO₂R₈ where n=1, 2,3, 4, NR₈COR₉, COR₈, CONR₈R₉ or CO₂R₈ where R₈ and R₉ are the same ordifferent and represent hydrogen or C₁-C₆ alkyl; or NR₈R₉ forms a 5-,6-, or 7-membered heterocyclic ring; or R₂ represents hydrogen or agroup of the formula

where R_(n) and R_(k) independently represent C₁-C₆ alkyl, C₂-C₆alkenyl, C₁-C₆ cycloalkyl (C₁-C₆)alkyl, benzoyl where the phenyl portionis optionally substituted with halogen, C₁-C₆ alkyl, or C₁-C₆ alkoxy; agroup of the formula IV-a

where p, s, and t independently represent 1 or 2; J is CH, N, O, or acarbon atom substituted with C₁-C₆ alkyl; or NR_(k)R_(n) represents

where s, t, and J are as defined above; R₃ represents C₁-C₆ alkyl,allyl, cyclopropylmethyl, cyclopentyl; or benzyl optionally mono-, di-,or trisubstituted independently with halogen, nitro, trifluoromethyl,trifluoromethoxy, cyano, or hydroxy; C₁-C₆ alkyl or C₁-C₆ alkoxy, eachof which is optionally substituted with amino, mono or di(C₁-C₆)alkylamino, a C₅-C₇ heterocycloalkyl group where the heteroatom isnitrogen and the nitrogen is attached to the parent alkyl portion;O(CH₂)_(n)CO₂R₈ where n=1, 2, 3, 4, NR₈COR₉, COR₈, CONR₈R₉ or CO₂R₈where R₈ and R₉ are the same or different and represent hydrogen orC₁-C₆ alkyl; NR₈R₉ forms a 5-, 6-, 7-membered heterocyclic ring; SO₂R₈,NHSO₂R₈, SO₂NHR₈, SO₂NHCOR₈, CONHSO₂R₈ where R₈ is defined as above;O(CH₂)_(n)—G where n=1,2,3,4 and G is SO₂R₈, NHSO₂R₈, SO₂NHR₈,SO₂NHCOR₈, or CONHSO₂R₈, where R₈ is as defined above; or tetrazole,triazole, imidazole, thiazole, oxazole, thiophene, or pyridyl; R₄, R₅and R₆ are the same or different and represent hydrogen; or C₁-C₆ alkylor C₁-C₆ alkoxy, each of which is optionally substituted with amino,mono or di(C₁-C₆) alkylamino, a C₅-C₇ heterocycloalkyl group where theheteroatom is nitrogen and the nitrogen is attached to the parent alkylportion, C₁-C₆ alkylthiol, or halogen; O(CH₂)_(n)CO₂R₈ where n=1, 2, 3,4, NR₈COR₉, COR₈, CONR₈R₉ or CO₂R₈ where R₈ and R₉ are the same ordifferent and represent hydrogen or C₁-C₆ alkyl; NR₈R₉ forms a 5-, 6-,or 7-membered heterocyclic ring; or R₄ and R₅ can form a 1,3-dioxolenering; X represents a bond, CH₂, or CH═CH; and A, B, C, and D are thesame or different and represent CH or N with the proviso that at leastone, but not more than two of A, B, C, or D represent N; b) washing thesample to remove unbound compound; and c) detecting the bound compound.2. A method for altering the signal-transducing activity of GABA_(A)receptors, the method comprising exposing cells expressing GABA_(A)receptors in vitro to a compound at a concentration sufficient toinhibit RO15-1788 binding to cells expressing a cloned human GABA_(A)receptor in vitro, wherein said compound has the formula:

or pharmaceutically acceptable salts thereof wherein: W represents

where Z is O, or S; R₁ represents phenyl, C₁-C₆ alkyl, cyclopentyl,cyclohexyl, benzyl, 3-fluorobenzyl, or cyclopropylmethyl; R₂ representshydroxyl; C₁-C₆ alkyl or C₁-C₆ alkoxy, each of which are optionallysubstituted with amino, mono or di(C₁-C₆) alkylamino, a C₅-C₇heterocycloalkyl group where the heteroatom is nitrogen and the nitrogenis attached to the parent alkyl portion; O(CH₂)_(n)CO₂R₈ where n=1, 2,3, 4, NR₈COR₉, COR₈, CONR₈R₉ or CO₂R₈ where R₈ and R₉ are the same ordifferent and represent hydrogen or C₁-C₆ alkyl; or NR₈R₉ forms a 5-,6-, or 7-membered heterocyclic ring; or R₂ represents hydrogen or agroup of the formula

where R_(n) and R_(k) independently represent C₁-C₆ alkyl, C₂-C₆alkenyl, C₁-C₆ cycloalkyl (C₁-C₆) alkyl, benzoyl where the phenylportion is optionally substituted with halogen, C₁-C₆ alkyl, or C₁-C₆alkoxy; a group of the formula IV-a

where p, s, and t independently represent 1 or 2; J is CH, N, O, or acarbon atom substituted with C₁-C₆ alkyl; or NR_(k)R_(n) represents

where s, t, and J are as defined above; R₃ represents C₁-C₆ alkyl,allyl, cyclopropylmethyl, cyclopentyl; or benzyl optionally mono-, di-,or trisubstituted independently with halogen, nitro, trifluoromethyl,trifluoromethoxy, cyano, or hydroxy; C₁-C₆ alkyl or C₁-C₆ alkoxy, eachof which is optionally substituted with amino, mono or di(C₁-C₆)alkylamino, a C₅-C₇ heterocycloalkyl group where the heteroatom isnitrogen and the nitrogen is attached to the parent alkyl portion;O(CH₂)_(n)CO₂R₈ where n=1, 2, 3, 4, NR₈COR_(9, COR) ₈, CONR₈R₉ or CO₂R₈where R₈ and R₉ are the same or different and represent hydrogen orC₁-C₆ alkyl; NR₈R₉ forms a 5-, 6-, 7-membered heterocyclic ring; SO₂R₈,NHSO₂R₈, SO₂NHR₈, SO₂NHCOR₈, CONHSO₂R₈ where R₈ is defined as above;O(CH₂)_(n)—G where n=1,2,3,4 and G is SO₂R₈, NHSO₂R₈, SO₂NHR₈,SO₂NHCOR₈, or CONHSO₂R₈, where R₈ is as defined above; or tetrazole,triazole, imidazole, thiazole, oxazole, thiophene, or pyridyl; R₄, R₅and R₆ are the same or different and represent hydrogen; or C₁-C₆ alkylor C₁-C₆ alkoxy, each of which is optionally substituted with amino,mono or di(C₁-C₆) alkylamino, a C₅-C₇ heterocycloalkyl group where theheteroatom is nitrogen and the nitrogen is attached to the parent alkylportion, C₁-C₆ alkylthiol, or halogen; O(CH₂)_(n)CO₂R₈ where n=1, 2, 3,4, NR₈COR_(9, COR) ₈, CONR₈R₉ or CO₂R₈ where R₈ and R₉ are the same ordifferent and represent hydrogen or C₁-C₆ alkyl; NR₈R₉ forms a 5-, 6-,or 7-membered heterocyclic ring; or R₄ and R₅ can form a 1,3-dioxolenering; X represents a bond, CH₂, or CH═CH; and A, B, C, and D are thesame or different and represent CH or N with the proviso that at leastone, but not more than two of A, B, C, or D represent N.
 3. A processfor the preparation of a compound of formula:

or a pharmaceutically acceptable salt thereof, wherein R₁ is phenyl,C₁-C₆ alkyl, cyclopentyl, cyclohexyl, benzyl, 3-fluorobenzyl,cyclopropylmethyl, or thienylmethyl; R₂ is hydrogen or halogen; R₃ isC₁-C₆ alkyl, allyl, cyclopropylmethyl, cyclopentyl, or benzyl, whereinthe benzyl group is optionally substituted with 1, 2, or 3 substituentsthat are independently halogen, nitro, trifluoromethyl,trifluoromethoxy, cyano, hydroxy, C₁-C₆ alkyl, C₁-C₆ alkoxy,—O(CH₂)_(n)—CO₂R₈, or —NR₈R₉; X is a bond, CH₂, or CH═CH; and W is

wherein R₄, R₅, and R₆ are independently hydrogen, halogen, C₁-C₆ alkyl,trifluoromethyl, trifluoromethoxy, C₁-C₆ alkoxy, —O(CH₂)_(n)—CO₂R₈, or—NR₈R₉, wherein the C₁-C₆ alkyl and the C₁-C₆ alkoxy are optionallysubstituted with NR₈R₉; R₈ and R₉ are independently hydrogen or C₁-C₆alkyl, wherein the C₁-C₆ alkyl is optionally substituted with C₁-C₆alkoxy or phenyl, wherein the phenyl is optionally substituted withhalogen, C₁-C₆ alkyl, trifluoromethyl, trifluoromethoxy, or C₁-C₆alkoxy; and n is 1, 2, 3, or 4; comprising (1) treating a compound offormula

with a compound of formula H₂N—R₃, to provide a compound of formula

(2) treating the product of (1) with a compound of formula Cl—C(O)—X—W,to provide a compound of formula


4. A method of preparing a compound of formula

or a pharmaceutically acceptable salt thereof, wherein R₁ is phenyl,C₁-C₆ alkyl, cyclopentyl, cyclohexyl, benzyl, 3-fluorobenzyl,cyclpropylmethyl, or thienylmethyl; R₃ is C₁-C₆ alkyl, allyl,cyclopropylmethyl, cyclopentyl, or benzyl, wherein the benzyl group isoptionally substituted with 1, 2, or 3 substituents that areindependently halogen, nitro, trifluoromethyl, trifluoromethoxy, cyano,hydroxy, C₁-C₆ alkyl, C₁-C₆ alkoxy, —O(CH₂)_(n)—CO₂R₈, or —NR₈R₉; X is abond, CH₂, or CH═CH; and W is

wherein R₄, R₅, and R₆ are independently hydrogen, halogen, C₁-C₆ alkyl,trifluoromethyl, trifluoromethoxy, C₁-C₆ alkoxy, —O(CH₂)_(n)—CO₂R₈, orNR₈R₉, wherein the C₁-C₆ alkyl and the C₁-C₆ alkoxy are optionallysubstituted with NR₈R₉; R₈ and R₉ are independently hydrogen or C₁-C₆alkyl, wherein the C₁-C₆ alkyl is optionally substituted with C₁-C₆alkoxy or phenyl, wherein the phenyl is optionally substituted withhalogen, C₁-C₆ alkyl, trifluoromethyl, trifluoromethoxy, or C₁-C₆alkoxy; comprising (1) treating 2-chloro-3-nitropyridine with a compoundof formula H₂N—R₁, to provide a compound of formula

(2) treating the product of (1) with hydrogen gas and Pd/C, or TiCl₃ andan acid, or SnCl₂ and an acid, to provide a compound of formula

(3) treating the product of (2) with RO—C(═NH)—CH₂Cl, wherein R is C₁-C₆alkyl, to provide a compound of formula

(4) treating the product of (3) with a compound of formula H₂N—R₃, toprovide a compound of formula

(5) treating the product of (4) with a compound of formula Cl—C(O)—X—W,to provide a compound of formula


5. A method of preparing a compound of formula

or a pharmaceutically acceptable salt thereof, wherein R₁ is phenyl,C₁-C₆ alkyl, cyclopentyl, cyclohexyl, benzyl, 3-fluorobenzyl,cyclpropylmethyl, or thienylmethyl; R₃ is C₁-C₆ alkyl, allyl,cyclopropylmethyl, cyclopentyl, or benzyl, wherein the benzyl group isoptionally substituted with 1, 2, or 3 substituents that areindependently halogen, nitro, trifluoromethyl, trifluoromethoxy, cyano,hydroxy, C₁-C₆ alkyl, C₁-C₆ alkoxy, —O(CH₂)_(n)—CO₂R₈, or —NR₈R₉; X is abond, CH₂, or CH═CH; and W is

wherein R₄, R₅, and R₆ are independently hydrogen, halogen, C₁-C₆ alkyl,trifluoromethyl, trifluoromethoxy, C₁-C₆ alkoxy, —O(CH₂)_(n)—CO₂R₈, or—NR₈R₉, wherein the C₁-C₆ alkyl and the C₁-C₆ alkoxy are optionallysubstituted with NR₈R₉; R₈ and R₉ are independently hydrogen or C₁-C₆alkyl, wherein the C₁-C₆ alkyl is optionally substituted with C₁-C₆alkoxy or phenyl, wherein the phenyl is optionally substituted withhalogen, C₁-C₆ alkyl, trifluoromethyl, trifluoromethoxy, or C₁-C₆alkoxy; and n is 1, 2, 3, or 4; comprising (1) treating4-chloro-3-nitropyridine with a compound of formula H₂N—R₁, to provide acompound of formula

(2) treating the product of (1) with hydrogen gas and Pd/C, or TiCl₃ andan acid, or SnCl₂ and an acid, to provide a compound of formula

(3) treating the product of (2) with RO—C(═NH)—CH₂Cl, wherein R is C₁-C₆alkyl, to provide a compound of formula

(4) treating the product of (3) with a compound of formula H₂N—R₃, toprovide a compound of formula

(5) treating the product of (4) with a compound of formula Cl—C(O)—X—W,to provide a compound of formula


6. A method of preparing a compound of formula

or a pharmaceutically acceptable salt thereof, wherein R_(A) and R_(B)are independently hydrogen or C₁-C₆ alkyl, wherein the C₁-C₆ alkyl isoptionally substituted with —NR₈R₉ or a heterocycyle wherein theheterocycle is morpholinyl, pyrrolidinyl, or piperidinyl, wherein theheterocycle is optionally substituted with C₁-C₆ alkyl or oxo; or R_(A)and R_(B) together form a heterocycle, wherein the heterocycle ismorpholine, pyrrolidine, piperidine, tetrahydropyridine,tetrahydroisoquinolinyl, wherein the heterocycle is optionallysubstituted with C₁-C₆ alkyl R₁ is phenyl, C₁-C₆ alkyl, cyclopentyl,cyclohexyl, benzyl, 3-fluorobenzyl, cyclpropylmethyl, or thienylmethyl;R₃ is C₁-C₆ alkyl, allyl, cyclopropylmethyl, cyclopentyl, or benzyl,wherein the benzyl group is optionally substituted with 1, 2, or 3substituents that are independently halogen, nitro, trifluoromethyl,trifluoromethoxy, cyano, hydroxy, C₁-C₆ alkyl, C₁-C₆ alkoxy,—O(CH₂)_(n)—CO₂R₈, or —NR₈R₉; X is a bond, CH₂, or CH═CH; and W is

wherein R₄, R₅, and R₆ are independently hydrogen, halogen, C₁-C₆ alkyl,trifluoromethyl, trifluoromethoxy, C₁-C₆ alkoxy, —O(CH₂)_(n)—CO₂R₈, or—NR₈R₉, wherein the C₁-C₆ alkyl and the C₁-C₆ alkoxy are optionallysubstituted with NR₈R₉; R₈ and R₉ are independently hydrogen or C₁-C₆alkyl, wherein the C₁-C₆ alkyl is optionally substituted with C₁-C₆alkoxy or phenyl, wherein the phenyl is optionally substituted withhalogen, C₁-C₆ alkyl, trifluoromethyl, trifluoromethoxy, or C₁-C₆alkoxy; and n is 1, 2, 3, or 4; comprising (1) treating a compound offormula

with tert-butyldimethylsilyl chloride and a base to provide a compoundof formula

(2) treating the product of (1) with hydrogen gas and Pd/C, or TiCl₃ andan acid, or SnCl₂ and an acid, to provide a compound of formula

(3) treating the product of (2) with RO—C(═NH)—CH₂Cl, wherein R is C₁-C₆alkyl, to provide a compound of formula

(4) treating the product of (3) with a compound of formula H₂N—R₃, toprovide a compound of formula

(5) treating the product of (4) with a compound of formula Cl—C(O)—X—W,to provide a compound of formula

(6) treating the product of (5) with tetrabutyl ammonium fluoride toprovide a compound of formula

(7) treating the product of (6) with thionyl chloride to provide acompound of formula

(8) treating the product of (7) with HNR_(A)R_(B) to provide a compoundof formula